KR20120028294A - Hazardous agent injection system - Google Patents

Abstract

An injection device comprising a powered injector and one or more dangerous agents is disclosed.

Description

HAZARDOUS AGENT INJECTION SYSTEM

This application, filed March 20, 2009, claims the benefit of US Provisional Patent Application 61 / 162,114, which is incorporated herein by reference for all purposes.

The present invention relates to injection of dangerous agents.

Since the late 1980s, risk agents, such as cytotoxic drugs, include rheumatoid arthritis (and other autoimmune diseases), combustor rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, steroid-resistant polymyositis or dermatitis, Wegener's granulomatosis, nodular polyarthritis, And several types of diseases such as vasculitis. Dangerous agents tend to have side effects, but they are harmful and toxic to the subject. Many of these side effects occur when dangerous agents are administered orally, but due to their ease of use, oral forms are generally the preferred method of administration of these agents.

In addition to increased toxicity, variable and reduced bioavailability has been observed for some dangerous agents such as methotrexate administered orally. This restriction is especially true when oral medications increase by more than 15 mg per week. This suggests that parenteral administration, such as injection, may lead to more predictable, reproducible and complex bioavailability, with better therapeutic results, especially at high doses.

Only about 7% of prescriptions for methotrexate, written by rheumatologists, are for injectable preparations. The reason for prescribing methotrexate injection is usually to improve bioavailability or alleviate side effects. Doctors have shown an interest in increasing the number of prescriptions for cytotoxic drug injections, especially injections for home and patient administration. This is not generally considered feasible, because the patient can easily and repeatedly extract the correct dosage from the vial and subcutaneous injection (SC) products such as drugs used to treat patients with certain debilitating diseases. This is because it is impossible to ensure precise administration by In addition, the toxicity of dangerous drugs increases the risk that non-users of injections will come into contact with cytotoxic drugs at home. There is not enough data on the effects of low doses or long-term exposure to dangerous agents that may or may be candidates for home or self-administration. Due to the lack of such information, care guidelines may be used to estimate high risks for injectable risk agents, such as methotrexate, with formal instruction and risk assessment recommendations, including formal education and mitigation strategies, to minimize risk. (Oliver, S., and Livermore, P., Administering subcutaneous methotrexate for inflammatory arthritis: RCN guidance for nurses, 2004; Royal College of Nursing, Wyeth, Publication Code 002 269). Special instructions for the manufacture of syringes in dedicated pharmacies with sterile manufacturing areas; Dosing performed only by individuals who are properly trained in special positions; An outflow kit disposed adjacent the area of use; Calculation of everything that could be dangerous in the event of an accident; And inspections to assess the implementation of complaints and risk mitigations. Due to the need for such instructions and, therefore, a number of precautions that must be learned and followed in order to safely inject dangerous drugs, for patients with dangerous drugs, in particular methotrexate, they can now take their own injections outside the hospital, without the help of a health care provider. It is thought that laying is impossible.

Therefore, an injector device that permits safe self-administration of a dangerous agent is useful, and an object of the present invention is to provide it.

In some embodiments, the risk agent is, but is not limited to, toxic drugs, cytotoxic drugs, high concentration drugs, drugs that have a large physiological effect at low doses, analgesics, immunomodulators, IL-1 receptor antagonists, IL-2 alpha receptor antagonists Anti-rejection compounds, hormones, prostaglandins, sedatives, anticholiners, Parkinson's disease treatments, expensive drugs, neuroleptics, tissue necrosis factor (TNF) blockers, and other risk agents. Such injector devices eliminate the risk of inadvertent contact of such agents with the subject and protect the non-user from contact with or exposure to the dangerous agent (s). Examples of cytotoxic agents include, but are not limited to, 6-mercaptopurine, 6-thioinosinic acid, azathioprine, chlorambucil, cyclophosphamide, cytophosphane, cytarabine, fluoroeuril, mel Palan, methotrexate, uramustine, anti-cytokine biological agents, cell receptor antagonists, cell receptor analogs and their respective derivatives and the like. Examples of highly concentrated agents include, but are not limited to: steroids such as dexamethasone, progesterone, somatostatin, and the like; Bioactive peptides such as teriparatide; And anticholinergic agents such as scopolamine. Examples of agents that have a physiological effect at low doses include, but are not limited to, antihypertensives and / or blood pressure lowering agents. Examples of analgesics are, but are not limited to, fentanyl, fentanyl citrate, morphine, meperidine and other narcotic analgesics. Examples of immunomodulatory agents include, but are not limited to adalimumab (antitissue necrosis factor monoclonal antibody or anti-TNF). Examples of IL-1 receptor antagonists include, but are not limited to anakinra. Examples of IL-2 receptor antagonists include, but are not limited to daclizumab and basiliximab. Examples of rejection suppression compounds include, but are not limited to, azathioprine, cyclosporine, and tacrolimus. Examples of hormones include but are not limited to testosterone, estrogen, growth hormone, insulin, thyroid hormone, follicle stimulating hormone (FSH), epinephrine / adrenaline, progesterone, paratyroid hormone, gonadotropin releasing hormone (GHRH), corpus luteum Forming hormone releasing hormone (LHRH), as well as other hormones that can cause side effects upon contact with hormones of opposite sexes, and derivatives thereof. Examples of prostaglandins include, but are not limited to, gamma-linolenic acid, docosahexanoic acid, arachidonic acid and eicosapentaenoic acid. Examples of sedatives include, but are not limited to: barbiturates such as amobarbital, pentobarbital, secobarbital and phenobarbitol; Benzodiazepines such as clonazepam, diazepam, estazolam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam, chlorodiazepoxide and alprazolam; Herbal sedatives such as ash bargain, Dubosia Hofudi, Prosanteria striatiflora, Caba (Piffer metasticum), Mandrake, Valerian and Marijuana; Non-benzodiazepine sedatives (a.k.a. "Z-drugs"), such as eszopiclone, zaleplon, zolpidem, jopiclones; Antihistamines such as diphenhydramine, dimenhydrinate, doxylamine and promethazine; It also includes other sedatives such as chloral hydrate. Examples of anticholinergic agents include, but are not limited to, dicyclomin, atropine, ipratropium bromide, oxytropium bromide, tiotropium, and the like. Examples of Parkinson's disease drugs include, but are not limited to, levodopa, dopamine, carbidopa, bengerazide, corseralpa, cobeneldopa, tolcapone, entacapone, bromocriptine, pergolide, pramipexole , Rofinirol, pyrivedyl, cabergoline, apomorphine, and lisuride. Examples of expensive medications include, but are not limited to, human growth hormone and erythropoietin. Examples of neuroleptic agents include, but are not limited to: antipsychotic agents; Butyrophenones such as haloperidol and droperidol; Chlorpromazine, Flufenazine, Perphenazine, Prochlorperazine, Thioridazine, Trifluoroperazine, Mesorazine, Ferricazine, Promazine, Triplelupromazine, Levomepromazine, Promethazine And phenothiazines such as picozide; Thioxanthenes such as chlorproticsen, clofentic sol, flufentic sol, thiotixene and zucopentisol; Atypical antipsychotic agents such as clozapine, olzapine, risperidone, quetiapine, ziprasidone, ammispriide, acenapine, paliperidone, iloperidone, jotepin and sertindol; Also included are third generation antipsychotic drugs such as aripiprazole and bifepronox. Examples of TNF blockers include, but are not limited to, etanercept.

In some embodiments, the risk agent is botulinum toxin, injectable gold, 6-mercaptopurine, 6-thioinosinic acid, azathioprine, chlorambucil, cyclophosphamide, cytophosphane, cytarabine, fluorouracil , Melphalan, methotrexate, uramustine, anti-cytokine biology, cell receptor antagonist, cell receptor analogues, dexamethasone, progesterone, somatostatin, analogues of dexamethasone, analogues of progesterone, analogues of somatostatin, teriparatide, scopolamine Antihypertensives, hypotensive agents, fentanyl, fentanyl citrate, morphine, meperidine, other narcotic analgesics, adalimumab (anti-tissue factor monoclonal antibody or anti-TNF), anakinra, daclizumab, Basiliximab, azathioprine, cyclosporin, tacrolimus, testosterone, estrogen, growth hormone, insulin, thyroid hormone, follicle stimulation Lemon (FSH), epinephrine / adrenaline, gamma-linolenic acid, docosahexanoic acid, arachidonic acid, eicosapentaenoic acid, amobarbital, pentobarbital, secobarbital, phenobarbitol, clonazepam, diazepam, es Tazolam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam, chlorodiazepoxide, alprazolam, ashbagenda, dubosia hofudi, prosantera stratiti Flora, Kava (Piper Methisticum), Mandrake, Valerian, Marijuana, Szopiclone, Zaleflon, Zolpidem, Zopiclon, Diphenhydramine, Dimenhydrinate, Doxylamine, Promethazine, Chloral Hydrates, dicyclomine, atropine, ifpratropium bromide, oxytropium bromide, thiotropium, levodopa, dopamine, carbidopa, bengerazide, coceral dopa, cobeneldopa, tolcapone, entacapone , Bro Lomocriptine, Pergolide, Pramipexole, Ropinillol, Pyribedil, Cabergoline, Apomorphine, Lisulide, Human Growth Hormone, Erythropoietin, Haloperidol, Droperidol, Chlorpromazine, Flu Phenazine, Perphenazine, Prochlorperazine, Thiolidazine, Trifluoroferazine, Mesorazine, Ferricazine, Proazine, Triplelupromazine, Levomepromazine, Promethazine, Pimozide, Chlor Proticesen, clofentic sol, flufentic sol, thioticesen, juclofentic sol, clozapine, olzapine, risperidone, quetiapine, ziprasidone, ammisulfide, acenapine, paliperidone, iloperidone, crude Teffin, sertindol, aripiprazole, bifepronox, etanercept, and derivatives of the aforementioned materials and combinations thereof.

In some embodiments, the dangerous agent includes pharmaceutically acceptable salts, solvates, hydrates, oxides or N-oxides thereof. In certain embodiments, the dangerous agent is a dangerous agent or a pharmaceutically acceptable salt, solvate, oxide or N-oxide thereof. In some embodiments the dangerous agent is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, oxide or N-oxide thereof.

In certain embodiments, the dangerous agent is methotrexate.

In one aspect, the present invention relates to a powered injector for safely self-injecting one or more agents within about 5 seconds. In various aspects, a patient may utilize self-injection risk agents by powered injectors. In certain embodiments, the powered injector is needle assisted. In certain embodiments, the powered injector is needle-free. In certain embodiments, the powered injector may utilize sufficient pressure to deliver a therapeutically effective amount of one or more dangerous agents in a complete and rapid manner within about 5 seconds. In certain embodiments, the powered injector may comprise a pre-filled syringe for accommodating one or more dangerous agents In certain embodiments, the powered injector comprises a pre-filled syringe and It may include a syringe sleeve to reduce injector impact by minimizing the movement of the injector by force In certain embodiments, the powered injector may include a needle exposure control element In certain embodiments, the powered injector May include safety measures to prevent post-injection hazards that may arise from bodily fluids contacting the dangerous agent directly or in contact with the dangerous agent In certain embodiments, the powered injector is a residual present in the injector component in contact with the dangerous agent. Safety measures to prevent the risk of post-injection arising from a dangerous agent.

In another aspect, the invention relates to a method of safely injecting one or more dangerous agents into a subject. In certain embodiments, the method utilizes a powered injection device having a prefilled syringe containing one or more medications that allows the subject to safely self administer within about 5 seconds. In certain embodiments, the method employs a spring powered injection device comprising a needle with means for controlling exposure of the needle during injection such that the exposure is sufficient to deliver one or more dangerous agents to appropriate tissue sites. It includes. In certain embodiments, the injector can have a spring strong enough to deliver one or more dangerous agents within about 2 seconds. In certain embodiments, the injector can have a syringe sleeve that minimizes movement of the syringe as a result of injection spring operation. In certain embodiments, the injector can have means for controlling needle exposure to lock after injection to prevent re-exposure of the needle. In certain embodiments, the injector may have a liquid sealing cap covering the means for controlling needle exposure, which may remove the cap in preparation of the injector for injection, and lock the injector upon reattachment after injection. To provide a container.

In some aspects, the present invention relates to an injection device. In various aspects, the injection device includes a powered injector configured to inject one or more drugs within about 5 seconds. In various aspects, a powered injector may comprise a container configured to receive a drug, a delivery member coupled to the container to inject the drug, a launch mechanism configured to release the drug from the fluid chamber through the delivery member to inject the drug, to perform an injection An energy source coupled to the launching mechanism to power the launching mechanism, and a trigger mechanism coupled to the launching mechanism to operate the launching mechanism. In some embodiments, the powered injector can be an autoinjector configured to inject one or more drugs within about 5 seconds. In some embodiments, the powered injector can be a jet injector. In some embodiments, the spray injector can be needle mounted. In some embodiments, the spray injector can be needleless.

In another aspect, the present invention is directed to an injection device, which device may comprise a powered injector configured to inject one or more dangerous agents within about 5 seconds. One embodiment of a powered injector is a container configured to receive a dangerous agent, a delivery member coupled to the container for injecting the dangerous drug, a launch mechanism configured to release the dangerous drug from the container through the delivery member for injecting the dangerous drug A source of energy coupled to the launching mechanism to power the launching mechanism to perform the injection, and a triggering mechanism coupled to the launching mechanism to operate the launching mechanism. The powered injector may be a single-shot injector and may be prefilled with a dangerous agent or alternatively have a cartridge that may be rechargeable or loaded into the injector for firing. Other embodiments may have adjustable doses.

In another embodiment, the present invention relates to an injection device that may include a jet injector and a compound of formula (I). One embodiment of a spray injector comprises a container configured to contain a dangerous agent comprising a compound of formula (I), an injection outlet member that is coupled to the container and configured to inject a dangerous drug, to inject a dangerous drug A launch mechanism configured to launch a dangerous agent from a fluid chamber through an injection outlet; an energy source coupled to the launch mechanism to power the launch mechanism; Includes a trigger mechanism to let. Injection injectors may be single-shot injectors and may be pre-filled with a hazardous agent or alternatively have a cartridge that may be rechargeable or loaded into the injector for firing. Other embodiments may have adjustable doses. In some embodiments, the dangerous agent is methotrexate or a pharmaceutically acceptable salt, solvate, hydrate, oxide or N-oxide thereof.

In another embodiment, the present invention relates to an injection device for the treatment of an inflammatory disease. In one embodiment, the injection device comprises a spray injector and a therapeutically effective amount of the drug, wherein the therapeutically effective amount of the drug is sufficient to treat an inflammatory disease. In some embodiments, the spray injector comprises a container configured to receive a drug; An injection outlet member coupled to the container for injecting the drug; a launching instrument configured to launch the drug from the fluid chamber through the outlet member for injecting the drug; An energy source for injection injection, and a trigger mechanism coupled to the launch mechanism to operate the launch mechanism. In some embodiments, the drug is a dangerous agent. In some embodiments, the drug is methotrexate or a pharmaceutically acceptable salt, solvate, hydrate, oxide or N-oxide thereof.

In another embodiment, the present invention relates to a kit. In some embodiments, the kit comprises a spray injector configured to inject a therapeutically effective amount of one or more dangerous agents within about 5 seconds, and instructions for using the spray injector with the dangerous agent. In some embodiments, the spray injector comprises a container configured to receive a hazardous agent, an injection outlet member coupled to the container for injecting the dangerous agent, a shot configured to launch the dangerous agent from the fluid chamber through the outlet member for injecting the dangerous agent An apparatus, an energy source coupled to the launching mechanism to energize the launching mechanism by injecting dangerous drugs from the injection outlet, and a trigger mechanism coupled to the launching mechanism to operate the launching mechanism. In one embodiment, the kit comprises a jet injector, a therapeutically effective amount of methotrexate contained in the jet injector, and instructions for injecting the methotrexate into the subject using the jet injector.

According to the present invention, there is provided an injector device that allows safe self-administration of dangerous drugs.

1 is a side view of an injection device according to an embodiment of the invention.
2 is a cross-sectional view of the injection device of FIG. 1 in a safe state taken along line AA.
3 is an enlarged view of a part of the cross-sectional view shown in FIG. 2.
4A and 4B are perspective views of the safety member used in connection with the injection device of FIG.
5 is a further cross-sectional view of the injection device of FIG. 1 in a safe state.
6A is a cross-sectional view of the injection device of FIG. 1 in a ready state.
6B is a cross-sectional view of the injection device of FIG. 1 at the start of the scanning state.
6C is a cross-sectional view of the injection device of FIG. 1 at the end of the scanning state.
6D is a sectional view of the injection device of FIG. 1 in a locked state.
7 is an exploded partial view of the trigger mechanism coupled to the device of FIG. 1.
8 is a perspective view of a needle guard according to an embodiment of the device of FIG. 1.
9 is a cross-sectional view of the cap shown in FIG.
10 is a graph showing the pressure in the liquid chamber of an injection device according to an embodiment of the present invention as a function of time.
11 is a cross-sectional view of a needleless injection scanning nozzle.
12 shows pharmacokinetic profiles of methotrexate in Göttingen mini pig plasma after subcutaneous injection of methotrexate and embodiments of the autoinjector of the present invention as a comparison to known hypodermic syringes.
FIG. 13 shows an average pharmacokinetic profile of methotrexate in Göttingen mini pig plasma after subcutaneous injection of methotrexate with an embodiment of the autoinjector of the present invention as a comparison to known hypodermic syringes.
14 shows an additional average pharmacokinetic profile of methotrexate in Göttingen mini pig plasma after subcutaneous injection of methotrexate with an embodiment of the autoinjector of the present invention as a comparison to known hypodermic syringes.
FIG. 15 shows a comparison of methotrexate exposure (C _max and AUC (0-t)) in Göttingen mini pig plasma after subcutaneous injection of methotrexate with an embodiment of the autoinjector of the present invention as a comparison to known hypodermic syringes.
Figure 16 shows a comparison of spring force during scanning between an embodiment of the autoinjector of the present invention and a known autoinjector.

Justice

"Acyl" refers to a -C (O) R radical, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, and the like. Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

"Acylamino" (or "acylamido") refers to an -NR'C (O) R radical, wherein R 'and R are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, as defined herein. , Aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl and the like. Representative examples include, but are not limited to, formylamino, acetylamino (ie, acetamido), cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino (ie, benzamido), benzylcarbonylamino, and the like. do.

"Alkoxy" refers to an -OR radical, where R is an alkyl or cycloalkyl group, as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

"Alkoxycarbonyl" refers to a -C (O) -alkoxy radical where alkoxy is according to the above definition.

"Alkyl" means a saturated or unsaturated, branched, straight or cyclic monovalent hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of the parental alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to methyl; Ethyl such as ethanyl, ethenyl and ethynyl; Propane-1-yl, propane-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1- Propyl such as yl (allyl) and cycloprop-1-en-1-yl; Cycloprop-2-en-1-yl, prop-1-en-1-yl-prop-2-en-1-yl and the like; Butan-1-yl, butan-2-yl, 2-methyl-1-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl , But-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1, 3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-diene Butyl such as -1-yl, boot-1-en-1-yl, boot-1-en-3-yl, but-3-en-1-yl and the like.

"Alkyl" is in particular a group having a certain saturation or saturation level, such as a group having a single single carbon-carbon bond alone, a group having at least one double carbon-carbon bond, a group having at least one triple carbon-carbon bond And groups having a mixture of single, double and triple carbon-carbon bonds. If a certain degree of saturation is intended, expressions such as "alkanyl" "alkenyl" and "alkynyl" are used. In certain embodiments the alkyl group contains 1 to 20 carbon atoms and in some embodiments includes 1 to 10 carbon atoms.

"Alkylamino" refers to a -NHR radical where R is an alkyl group or cycloalkyl according to the above definition. Representative examples include, but are not limited to, methylamino, ethylamino, 1-methylethylamino, cyclohexyl amino, and the like.

"Alkylsulfinyl" refers to the radical -S (O) R wherein R is an alkyl group or a cycloalkyl group according to the above definition. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like.

"Alkylsulfonyl" refers to the radical -S (O) ₂ R wherein R is an alkyl group or a cycloalkyl group according to the above definition. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

"Alkylthio" refers to an -SR radical wherein R is an alkyl group or a cycloalkyl group according to the above definition. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio and the like.

"Amino" refers to the -NH ₂ radical.

"Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, aceanthryl, acenaphthylene, acefenanthryl, anthracene, azulene, benzene, chrysene, coronene, fluoroanthene, fluorene, hexacene, hexaphene, hexaene, as -Indene, S-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, pentalene, Phenanthrene, pisene, playaden, pyrene, pyrantrene, rubisen, triphenylene, trinaphthalene and the like. In certain embodiments the aryl group contains 6-20 carbon atoms and in some embodiments contains 6-12 carbon atoms.

"Arylalkyl" refers to an acyclic alkyl group in which one of a carbon atom, usually a terminal carbon atom or a hydrogen atom bonded to an sp ³ carbon atom, is substituted with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene- 1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. As the scientific name considering the alkyl moiety, in particular arylalkanyl, arylalkenyl and / or arylalkynyl and the like are used. In certain embodiments the arylalkyl group is a (C ₆ -C ₃₀ ) arylalkyl, such as the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C ₁ -C ₁₀ ) and the aryl moiety is (C ₆ -C ₂₀ ) And in some embodiments the arylalkyl group is a (C ₆ -C ₂₀ ) arylalkyl such as the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C ₁ -C ₈ ) and the aryl moiety is (C _6- C ₁₂ ).

"Aryloxy" refers to an -OR radical and R represents an aryl group according to the above definition.

"AUC", as defined herein, refers to the lower area of a curve that represents the concentration of a compound, such as a dangerous agent, or a blood or plasma metabolite thereof in a patient as a function of time after patient administration of the compound. For example, the administering compound may be a dangerous agent according to the above definition. AUC measures the concentration of the compound or its metabolites in the blood at various time intervals according to methods such as liquid chromatography-serial mass spectrometry (LC / MS / MS), and the lower area of the blood or plasma concentration-versus-time curve Can be determined by calculating Concentration versus time-curve is also called pharmacokinetic profile. Suitable methods for calculating AUC from compound concentration-versus-time curves are well known in the art. For example, the AUC of a dangerous drug methoxtrexate can be determined by measuring methotrexate to a patient and measuring its blood concentration. AUC _{0 -24} is a bottom area of the curve up to 24 hours (0 time) after administration. AUC _{SS , 24} is the lower area of the 24 hour curve (normal) after dosing regimen administered for a period of time.

"Bioavailability" refers to the amount of a compound that is determined by administering a compound, such as a dangerous agent, to a patient and then reaching the systemic circulation of the compound to assess the compound's, eg, blood or plasma concentrations. For example, the administering compound may be a dangerous agent according to the above definition.

"Compound" herein includes compounds in the formula (I) range. Compounds may be defined by their chemical structure and / or chemical name. If the chemical structure and the chemical name conflict with each other, the chemical structure determines the definition of the compound. The compounds herein may have one or more chiral centers and / or double bonds and therefore exist in stereoisomeric forms such as double bond isomers (ie, geometric isomers), enantiomers or diastereomers. Thus, unless otherwise stated, any chemical structure is within the scope defined herein, in whole or in part, and in the relevant technical constructions, stereoisomeric pure forms (e.g., geometric pure, enantiomeric pure, or diastereomeric pure) It also encompasses all possible enantiomers and stereoisomers of the compounds exemplified herein, including their enantiomeric and diastereomeric mixtures. Enantiomeric and stereoisomeric mixtures can be decomposed into constituent enantiomers or stereoisomers according to methods well known to those skilled in the art, such as separation techniques or chiral synthesis methods. For example, decomposition of enantiomers or diastereomers can be accomplished by conventional methods such as crystallization reactions in the presence of disintegrants or by chromatography using chiral high pressure liquid chromatography (HPLC) columns.

The compounds disclosed herein also exist in a number of tautomeric forms, including enol forms, keto forms, mixtures thereof, and the like. Thus, the chemical structures shown herein include all possible tautomeric forms of the compounds shown. Compounds herein include compounds of isomeric labels having one or more valences having an atomic weight that is different from the atomic weight of the naturally occurring generator. Examples of isomers that can be incorporated into the compounds disclosed herein include, but are not limited to, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ^'15 N, ¹⁸ O, ¹⁷ O, and the like. The compounds may exist in both unsolvated and solvated forms and include hydrated forms and oxides or N-oxides. In general, the compounds are free acids, hydrates, solvates, oxides or N-oxides. The compounds may exist in multiple crystalline or coexistent crystalline or amorphous forms. The compound includes pharmaceutically acceptable salts or solvates of the free acid form of any of the materials described above, as well as crystalline forms of the material. The compound also includes solvates.

"Cycloalkyl" refers to a saturated or unsaturated cyclic alkyl radical. With respect to a given degree of saturation, the chemical name is "cycloalkanyl" or "cycloalkenyl". Common cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In certain embodiments the cycloalkyl group is (C ₃ -C ₁₀ ) cycloalkyl and in some embodiments is (C ₃ -C ₇ ) cycloalkyl.

"Cycloheteroalkyl" is a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and hydrogen atoms linked thereto) are independently substituted with one another by the same or different heteroatoms. Typical heteroatoms for substituting the carbon atom (s) include, but are not limited to, N, P, O, S, Si, and the like. Regarding a given saturation, the chemical name uses "cycloheteroalkanyl" or "cycloheteroalkenyl". Typical cycloheteroalkyl groups include, but are not limited to, epoxides, imidazolidines, morpholines, piperazine, piperidine, pyrazolidines, pyrrolidines, quinuclidines and the like.

"Dialkylamino" refers to the radical -NRR 'wherein R and R' independently of one another represent an alkyl or cycloalkyl group according to the above definition. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di- (1-methylethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl) amino, (cyclohexyl) (propyl) amino, etc. It includes.

“Formula (I)” includes methotrexate derivative (I), pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable oxides, and crystalline forms of such materials. Formula (I) is used complementarily with the compound of formula (I). In certain embodiments, the compound of formula (I) can be a free acid. In certain embodiments, the compound of formula (I) may be a pharmaceutically acceptable salt.

"Halo" refers to fluoro, chloro, bromo or iodo.

"Dangerous drugs" are toxic drugs, cytotoxic drugs, and / or other dangerous and high-concentration drugs that can have serious effects on contact with the subject, drugs that have a large physiological effect at low doses, immunomodulators, IL- 1 receptor antagonists, IL-2 alpha receptor antagonists, rejection inhibitors, hormones, prostaglandins, sedatives, anticholiners, Parkinson's disease drugs, expensive drugs, neuroleptics, tissue necrosis factor (TNF) blockers, and other risk agents As one or more medicaments. In the present specification, there is no particular limitation, but "dangerous drug (s)" may be used complementarily with "drug" and "drug". Dangerous agents include, but are not limited to, antineoplastic cytotoxic agents, anesthetics, antiviral agents, highly concentrated peptide compounds, toxic agents, cytotoxic agents, highly concentrated agents, agents that have large physiological effects at low doses, immunomodulators, IL-1 receptors Antagonists, rejection inhibitors, hormones, prostaglandins, sedatives, anticholiners, Parkinson's disease drugs, expensive drugs, neuroleptics, tissue necrosis factor (TNF) blockers, and other risk agents, especially toxic drugs, There are cytotoxic drugs, highly concentrated drugs, and drugs that have a large physiological effect at low doses.

Examples of highly concentrated drugs include, but are not limited to, steroids such as dexamethasone, progesterone, somatostatin, and the like; Bioactive peptides such as teriparatide; And anticholinergic agents such as scopolamine. Examples of agents that have a physiological effect at low doses include, but are not limited to, antihypertensives and / or blood pressure lowering agents. Examples of analgesics are, but are not limited to, fentanyl, fentanyl citrate, morphine, meperidine and other narcotic analgesics. Examples of immunomodulatory agents include, but are not limited to adalimumab (antitissue necrosis factor monoclonal antibody or anti-TNF). Examples of IL-1 receptor antagonists include, but are not limited to anakinra. Examples of IL-2 receptor antagonists include, but are not limited to daclizumab and basiliximab. Examples of rejection suppression compounds include, but are not limited to, azathioprine, cyclosporine, and tacrolimus. Examples of hormones include but are not limited to testosterone, estrogen, growth hormone, insulin, thyroid hormone, follicle stimulating hormone (FSH), epinephrine / adrenaline, progesterone, paratyroid hormone, gonadotropin releasing hormone (GHRH), corpus luteum Forming hormone releasing hormone (LHRH), as well as other hormones that can cause side effects upon contact with hormones of opposite sexes, and derivatives thereof. Examples of prostaglandins include, but are not limited to, gamma-linolenic acid, docosahexanoic acid, arachidonic acid and eicosapentaenoic acid. Examples of sedatives include, but are not limited to: barbiturates such as amobarbital, pentobarbital, secobarbital and phenobarbitol; Benzodiazepines such as clonazepam, diazepam, estazolam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam, chlorodiazepoxide and alprazolam; Herbal sedatives such as ash bargain, Dubosia Hofudi, Prosanteria striatiflora, Caba (Piffer metasticum), Mandrake, Valerian and Marijuana; Non-benzodiazepine sedatives (a.k.a. "Z-drugs"), such as eszopiclone, zaleplon, zolpidem, jopiclones; Antihistamines such as diphenhydramine, dimenhydrinate, doxylamine and promethazine; It also includes other sedatives such as chloral hydrate. Examples of anticholinergic agents include, but are not limited to, dicyclomin, atropine, ipratropium bromide, oxytropium bromide, tiotropium, and the like. Examples of Parkinson's disease drugs include, but are not limited to, levodopa, dopamine, carbidopa, bengerazide, corseralpa, cobeneldopa, tolcapone, entacapone, bromocriptine, pergolide, pramipexole , Rofinirol, pyrivedyl, cabergoline, apomorphine, and lisuride. Examples of expensive medications include, but are not limited to, human growth hormone and erythropoietin. Examples of neuroleptic agents include, but are not limited to: antipsychotic agents; Butyrophenones such as haloperidol and droperidol; Chlorpromazine, Flufenazine, Perphenazine, Prochlorperazine, Thioridazine, Trifluoroperazine, Mesorazine, Ferricazine, Promazine, Triplelupromazine, Levomepromazine, Promethazine And phenothiazines such as picozide; Thioxanthenes such as chlorproticsen, clofentic sol, flufentic sol, thiotixene and zucopentisol; Atypical antipsychotic agents such as clozapine, olzapine, risperidone, quetiapine, ziprasidone, ammispriide, acenapine, paliperidone, iloperidone, jotepin and sertindol; Also included are third generation antipsychotic drugs such as aripiprazole and bifepronox. Examples of TNF blockers include, but are not limited to, etanercept.

Dangerous agents include pharmaceutically acceptable salts, solvates, hydrates, oxides or N-oxides thereof. In certain embodiments, the dangerous agent is a cytotoxic compound or a pharmaceutically acceptable salt, solvate, oxide or N-oxide thereof. In certain embodiments the dangerous agent is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, oxide or N-oxide thereof.

In certain embodiments, the drug is methotrexate.

In certain embodiments, the risk agent is botulinum toxin, injectable gold, 6-mercaptopurine, 6-thioinosinic acid, azathioprine, chlorambucil, cyclophosphamide, cytophosphane, cytarabine, fluorouracil , Melphalan, methotrexate, uramustine, anti-cytokine biology, cell receptor antagonist, cell receptor analogues, dexamethasone, progesterone, somatostatin, analogues of dexamethasone, analogues of progesterone, analogues of somatostatin, teriparatide, scopolamine Antihypertensives, hypotensive agents, fentanyl, fentanyl citrate, morphine, meperidine, other narcotic analgesics, adalimumab (anti-tissue factor monoclonal antibody or anti-TNF), anakinra, daclizumab, Basiliximab, azathioprine, cyclosporin, tacrolimus, testosterone, estrogen, growth hormone, insulin, thyroid hormone, follicle stimulation Lemon (FSH), epinephrine / adrenaline, gamma-linolenic acid, docosahexanoic acid, arachidonic acid, eicosapentaenoic acid, amobarbital, pentobarbital, secobarbital, phenobarbitol, clonazepam, diazepam, es Tazolam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam, chlorodiazepoxide, alprazolam, ashbagenda, dubosia hofudi, prosantera stratiti Flora, Kava (Piper Methisticum), Mandrake, Valerian, Marijuana, Szopiclone, Zaleflon, Zolpidem, Zopiclon, Diphenhydramine, Dimenhydrinate, Doxylamine, Promethazine, Chloral Hydrates, dicyclomine, atropine, ifpratropium bromide, oxytropium bromide, thiotropium, levodopa, dopamine, carbidopa, bengerazide, coceral dopa, cobeneldopa, tolcapone, entacapone , Bro Lomocriptine, Pergolide, Pramipexole, Ropinillol, Pyribedil, Cabergoline, Apomorphine, Lisulide, Human Growth Hormone, Erythropoietin, Haloperidol, Droperidol, Chlorpromazine, Flu Phenazine, Perphenazine, Prochlorperazine, Thiolidazine, Trifluoroferazine, Mesorazine, Ferricazine, Proazine, Triplelupromazine, Levomepromazine, Promethazine, Pimozide, Chlor Proticesen, clofentic sol, flufentic sol, thioticesen, juclofentic sol, clozapine, olzapine, risperidone, quetiapine, ziprasidone, ammisulfide, acenapine, paliperidone, iloperidone, crude Tepin, sertindol, aripiprazole, bifepronox, etanercept, derivatives of the aforementioned materials, combinations thereof, and the like.

Dangerous agents can cause death and / or cause serious side effects such as cancer, infection, organ toxicity, miscarriage, genetic damage and birth defects. Risk agents are also acute and less severe, but they also have mechanisms of action that may be harmful to the patient, such as a compromised immune system. Lowering immunity is caused by a decline in certain cell populations or their actions involved in an immune response, which increases susceptibility to infection, that is, is easily infected. Lowering the immune system is potentially harmful, but may be beneficial for patients with autoimmune diseases as it can act to reduce inflammation in the patient.

"Heteroalkyloxy" refers to an -O-heteroalkyl group where heteroalkyl is as defined above.

"Heteroalkyl" refers to each alkyl, alkanyl, alkenyl and alkynyl radical in which one or more carbon atoms (and hydrogen atoms linked thereto) are each independently replaced with the same or different heteroatom groups. Typical heteroatomic groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, -NR'-, = NN =, -N = N-, -N = N-NR '-, -PH-, -P (O) _2- , -OP (O) _2- , -S (O)-, -S (0) _2- , -SnH _2- , etc., wherein R' Is hydrogen, alkyl, cycloalkyl or aryl.

"Heteroaryl" refers to a monovalent heteroaromatic radical derived by removing one hydrogen atom from a single atom of the parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to; Acridine, argindol, carbazole, P-carboline, chromman, chromene, cynoline, furan, imidazole, indazole, indole, indolin, indolizine, isobenzofuran, isochromen, isoindole Isoindolin, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran , Pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidinine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiaphen, triazole, xanthan And groups derived from the like. In some embodiments the heteroaryl group is 5- to 20-membered heteroaryl and in some embodiments 5- to 10-membered heteroaryl. In some embodiments the heteroaryl group may be derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

"Heteroarylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal carbon atom or an sp ³ carbon atom, is substituted with a heteroaryl group. As scientific names considering certain alkyl moieties, in particular heteroarylalkanyl, heteroarylalkenyl and / or heteroarylalkynyl and the like are used. In some embodiments the heteroarylalkyl group is 6- to 30-membered heteroarylalkyl, such as the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1- to 10-membered and the heteroaryl moiety is 5--20 -Membered heteroaryl. In some embodiments, 6- to 20-membered heteroarylalkyl, such as the alkanyl, alkenyl or alkynyl moiety of heteroarylalkyl, is 1- to 8-membered and the heteroaryl moiety is 5- to 12-membered heteroaryl to be.

"Heteroaryloxy" refers to an -O-heteroaryl group where heteroaryl is defined as described above.

"N-oxide" (also known as "amine oxide" and "amine-N-oxide") is a chemical compound containing a functional group R ₃ N ⁺ -O ^- wherein R is hydrogen, alkyl, aryl, arylalkyl, cyclo Alkyl, cycloheteroalkyl, heteroalkyl, heteroaryl or heteroarylalkyl.

"Oxoxide" refers to a chemical compound that contains at least one oxygen atom and at least one other element.

"Patient" and "subject" refer to a mammal, such as a human, independently of one another.

"Pharmaceutically acceptable" means that it is listed in the United States Pharmacopoeia or any other recognized pharmacopeia applicable to mammals, including humans, and licensed or approved by federal or state departments.

"Pharmaceutically acceptable salt" means a salt of a compound, such as a salt of a dangerous agent, that retains the desired pharmacokinetic activity of the parent compound and is pharmaceutically acceptable. Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; Or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamon Acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-headoxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-Methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydride Acid addition salts formed using organic acids such as oxynaphthoic acid, salicylic acid, stearic acid and muconic acid; And (2) acidic protons present in the parent compound are replaced with metal ions, such as alkali metal ions, alkaline earth metal ions or aluminum ions; Or salts formed by coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. In certain embodiments the salt of the dangerous agent is hydrogen chloride, in some embodiments the sodium salt.

A "pharmaceutically acceptable vehicle" or "pharmaceutically acceptable excipient" is a pharmaceutically acceptable diluent, pharmaceutically acceptable adjuvant, pharmaceutically acceptable excipient, pharmaceutically acceptable carrier, or combination thereof. As water, a compound, such as a substance that is administered to a patient when administered to a patient and which is harmless to the patient when administered in an amount sufficient to provide a therapeutically effective amount of the compound without destroying the pharmaceutical activity of the drug .

"Drug dynamics" is to evaluate the behavior of a drug to be administered to the human body. Variables used to characterize pharmacokinetics include blood concentration-versus-time curves, area under the curve (AUC), time versus peak concentration (T _max ), and compound maximum concentration (C _nax ), where C _max Is the maximum concentration of the compound in the patient's plasma after administration of the compound to a patient, and T _max is also the maximum concentration (C _max ) of the compound in the patient's plasma after the administration of the predetermined amount of the compound to the patient. It's time.

"Powered injector" refers to an injection device equipped with an energy source that will power a mechanism for operating the injector. The powered injector herein is configured to deliver or inject one or more dangerous agents to the subject within about 5 seconds.

"Solvate" refers to a molecular complex in which a compound is combined with one or more solvent molecules in stoichiometric or non-stoichiometric amounts. Such solvent molecules are commonly used in the pharmaceutical field, and water, ethanol, and the like, which are toxic to a patient, are known. Molecular complex salts between a compound or part of a compound and a solvent may be stabilized by noncovalent intramolecular forces such as electromagnetic forces, van der Waals forces, or hydrogen bonding. "Hydrate" refers to a solvate wherein at least one solvent molecule is water.

A "therapeutically effective amount" refers to an amount sufficient to exert a therapeutic effect on a disease or condition or clinical condition when administered to a subject to treat at least one clinical condition of the disease or condition. A therapeutically effective amount can be, for example, the type of compound, disease or condition and / or condition of the disease or condition, the severity of the disease or condition and / or condition, age, weight and / or health condition of the patient being treated, and also the prescribing physician. It may vary depending on the judgment. A therapeutically effective amount can be ascertained by those skilled in the art or can be determined through routine experimentation.

"Treating" or "treatment" of a disease is alleviating or alleviating at least one clinical condition of a disease or disorder or disease or disorder, risk of developing at least one clinical condition of such disease or disorder or disease or disorder Reducing the risk of, or reducing the progression of, disease or disease or at least one clinical condition of the disease or condition, or reducing the risk of progression of the disease or disease or at least one clinical condition of the disease or condition. Say. "Treating" or "treatment" also inhibits a disease or condition, physically (eg, stabilizing identifiable symptoms), mentally (eg, stabilizing physical variables) or both, and is also recognizable to the patient. It also includes suppressing one or more physical variables that may or may not be recognizable. In certain embodiments, "treating" or "treatment" means that the disease or at least one symptom of the disease in a patient expected to be exposed to, or expected to suffer, the disease or disease, even if the disease has not been experienced or indicated yet. To delay the onset of disease.

Examples, including but not limited to, dangerous agents, injectors, and injection methods, are described in detail as follows. Such embodiments do not limit the scope of the present application. Rather, the claims herein are intended to cover all modifications, modifications and equivalents of these examples.

Injection of dangerous drugs

In various aspects, the present invention relates to injection of a dangerous agent. In certain embodiments the risk agent is a cytotoxic agent. Examples of cytotoxic agents that can be used in the present invention include, but are not limited to, 6-mercaptopurine, 6-thioinosine acid, azathioprine, chlorambucil, cyclophosphamide, cytophosphane, cytarabine, Melphalan, methotrexate, uramustine, anti-tissue necrosis factor biologics, anti-cytokine biologics, cell receptor antagonists, cell receptor analogs and their respective derivatives and the like. Some of these drugs are labeled "cytotoxic," because they act directly to kill cells or participate in metabolism. Cytotoxic agents acting in this way have the greatest impact against rapidly dividing cells. For rapidly dividing tumor cells, cytotoxic agents kill these cells and are therefore particularly effective. This activity can also inhibit cells involved in an overactive immune response and consequently reduce the activation of the disease, thus the cytotoxic agents can prevent rheumatoid arthritis (and other autoimmune diseases), lupus, vasculitis and related diseases. It can be cured. The basic mechanism of action described above is to suppress an overactive immune response, resulting in an anti-inflammatory effect. For example, when treating a disease at low doses, the active action of the cytotoxic drug methotrexate is anti-inflammatory, not cytotoxic.

In some embodiments, one or more dangerous agents and / or pharmaceutically acceptable salts, solvates, hydrates, oxides and N-oxides thereof can be injected within about 5 seconds using a powered injector. In some embodiments, the disclosure relates to the injection of one or more dangerous agents and one or more pharmaceutically acceptable excipients. In some embodiments, directed to injecting pharmaceutically acceptable salts of one or more dangerous agents.

Methotrexate  And injection of derivatives thereof

In some embodiments, the dangerous agent injected is one or more derivatives of methotrexate and / or methotrexate represented by formula (I): In one aspect, the invention discloses injecting methotrexate and / or a derivative of methotrexate within 5 seconds via a powered injector. In some embodiments, methotrexate and / or derivatives of methotrexate and / or pharmaceutically acceptable salts, solvates, hydrates, oxides and N-oxides thereof are injected. In some embodiments, the invention discloses injecting methotrexate and / or derivatives of methotrexate with one or more pharmaceutically acceptable excipients. In some embodiments, the present invention also discloses injecting pharmaceutically acceptable salts of methotrexate and / or derivatives of methotrexate. In some embodiments, the invention discloses injecting a pharmaceutical composition comprising methotrexate and a pharmaceutically acceptable excipient.

Jet injection of dangerous drugs

In some embodiments, the invention discloses injecting a dangerous agent through a spray injector. In some embodiments, the jet injector is a needle mounted jet injector. In certain embodiments, the spray injector is a needleless injector. In certain embodiments, dangerous agents and / or pharmaceutically acceptable salts, solvates, hydrates, oxides and N-oxides thereof are injected. In some embodiments, a pharmaceutical composition is injected that includes one or more dangerous agents and one or more pharmaceutically acceptable excipients. In some embodiments, a pharmaceutically acceptable salt of a risk agent is injected. In some embodiments, the invention describes an injection of a pharmaceutical composition comprising methotrexate and a pharmaceutically acceptable excipient.

compound

In various aspects, the present invention relates to dangerous drugs. In various embodiments, the present invention describes compounds represented by the following formula (I) and pharmaceutically acceptable salts, solvates, hydrates, oxides and N-oxides thereof.

In various aspects, R ₁ , R ₂ and R ₃ are each independently hydrogen, alkyl, alkoxy, acyl, acylamino, alkylamino, alkylsulfinyl, alkylsulfonyl, alkylthio, alkoxycarbonyl, aryl, arylalkyl, Aryloxy, cycloalkyl, cycloheteroalkyl, dialkylamino, halo, heteroalkyl, heteroaryl, heteroarylalkyl, heteroalkyloxy and heteroaryloxy.

In certain embodiments, the compound of formula (I) is a cytotoxic drug methotrexate, wherein R ₁ is methyl and R ₂ and R ₃ are both hydrogen. In the chemical name, methotrexate is known as L-(+)-N- [p-[[(2,4-diamino-6-p-terridinyl) methyl] methylamino] -benzoyl] glutamic acid and is a phylogenetic name (IUPAC ) Is (2S) -2-[(4-{[(2,4-diamino-7,8-dihydrophterridin-6-yl) methyl] (methyl) amino} phenyl) formamino] pentanedione It is a mountain.

In certain embodiments, compounds of Formula (I) may be prepared by the methods according to US Pat. No. 4,374,987 to Singh et al. And 4,080,325 to Ellard.

The risk agent of the present invention may comprise a therapeutically effective amount of one or more of the risk agents disclosed herein, and in some embodiments is suitable for direct self-administration by the patient using an appropriate amount of a pharmaceutically acceptable vehicle in the form of a pure substance together with an appropriate amount. It can be prepared in the form. In some embodiments, the risk agent and pharmaceutically acceptable vehicle of the present invention are sterile upon self-administration of the patient. In some embodiments, water may be used as the vehicle for autoinjection of the dangerous agents of the present invention. In some embodiments, saline and aqueous solutions of dextrose and glycerol may also be used as liquid vehicles for injection. Suitable pharmaceutical vehicles may also include excipients such as sodium phosphate, sodium citrate, sodium acetate trihydrate, citric acid, glacial acetic acid, mannitol, polysorbate 80, L-arginine hydrochloride, methacresol, phenol, zinc oxide and water have. In some embodiments, the risk agents of the present invention may also include small amounts of wetting or emulsifying agents, pH buffers and / or adjuvants, stabilizers, thickeners, lubricants and / or colorants, and the like.

In some embodiments, a pharmaceutical composition provided by the present invention is one comprising a risk agent disclosed herein in combination with one or more pharmaceutically acceptable excipients.

The amount of one or more pharmaceutically acceptable excipients included in the pharmaceutical composition may be, for example: 0.005% to 10% by weight; It can also be from 2 to 6 weight percent per volume, as weight percent per volume (% w / v) based on the total weight of excipient per unit volume.

In some embodiments, the pharmaceutical compositions provided by the present invention comprise pharmaceutically acceptable salts of the dangerous agents disclosed herein.

Pharmacokinetics

In general, the bioavailability of the similar drug is 100 because the dangerous drug is not destroyed in the gastrointestinal tract or disappears in the body during injection or intravenous administration, and also does not go through tissue composition or components before systematic use when the dangerous drug is injected into the tissue. Close to% By changing the route of administration of the dangerous agent, the pharmacokinetics of the dangerous agent also change, so that the pharmacokinetics and / or bioavailability of the dangerous agent can be maintained according to individual methods suitable for the patient, dosage, or other characteristics of the dangerous agent.

In certain embodiments, the bioavailability of the dangerous agent may be maintained at or near a known or appropriate level by selecting one or more factors in the construction of the powered injector. Also in certain embodiments, one or more factors of injector configuration may be selected to maintain bioequivalence of the dangerous agent. Bioequivalence can also be measured according to known means for measuring plasma concentration, thereby determining the absorption rate and degree of absorption of the dangerous agent. The degree of absorption can also be determined by determining the AUC of the dangerous agent. C _max concentrations can also be used to determine risk drug uptake. Bioequivalence assumes that a dangerous agent injected through the injector of the present invention reaches an absorption site in a similar time and is absorbed to about the same extent as when the dangerous agent was introduced through other known routes of administration. Risk agents typically reach bioequivalence when one or more confidence intervals of the measured pharmacokinetic parameters fall within the range of about 80% to 125% of the known or required risk agent concentration. (See Approved Compound Products With Therapeutic Equivalence Evaluations, US Food and Compound Administration Electronic Orange Book, 27th ed.Washington, DC: US Department of Health & Human Services (2007); and 21 CFR§ 320.33 (April 1, 2005))

The rate of injection or the rate at which the dangerous agent is delivered to the subject is a function of a number of characteristics of the injector used, including but not limited to the pressure used in the injector during injection and / or the outlet of the injection outlet of the injection outlet member in the injector, such as It is a function of the configuration and size of the needle or needleless nozzle used. In some embodiments, the injection rate of the injector may be at a similar level of risk as in other parenteral delivery methods, including but not limited to, eg, injection through conventional subcutaneous syringes, by varying the pressure exerted on the injector to inject the dangerous agent. Selected to maintain pharmacokinetics and / or bioavailability of the agent.

Since the interaction of the dangerous agent ejected from the injector of the present invention can vary widely from subject to subject, it is also necessary to change one or more factors in the injector configuration. The pattern of deposition of dangerous agents following injection suggests that increased dispersibility from powered injectors, when compared to bolus deposition of manual syringes, affects the interaction between cells and dangerous agents and also moves the system within the system circulation of the dangerous agent. It is worth noting that it may promote or hinder For example, in the case of dangerous drug methotrexate, a cell transport mechanism is present so that the cells absorb methotrexate, which includes a membrane transport protein called a reducing hydrochloric acid carrier and a folate receptor. This mechanism has a variable rate of action and variable expression (see Kremer, J.M., Toward a better understanding of methotrexate, Arthritis and Rheumatism 2004; 50: 1370-1382). Likewise, since methotrexate encounters these cells after injection and prior to entering the systemic circulation, the pharmacokinetics and / or bioavailability of methotrexate varies greatly from subject to subject. Therefore, the amount of change in one or more factors in the injector configuration depends at least in part on the nature of the disease, the subject to be treated and the prescriber's discretion. It may also be determined through known standard techniques.

With the powered injectors herein, the dangerous agent can be injected to the subject more precisely and within about 5 seconds more fully than when using a manual syringe. In the example of a jet injector, the configuration of such a jet injector, the factors affecting injection, etc., are the same or substantially the same as those identified when using parenteral delivery methods, including but not limited to conventional manual hypodermic syringes. Choose appropriately to get the _max value. In another embodiment of the injection injector, the configuration of such injection injectors, the factors affecting injection, etc., are the same or substantially the same risks as identified when using parenteral delivery methods, including but not limited to conventional manual hypodermic syringes. Select appropriately to get the T _max value of the drug. In another example of an injection injector, the configuration of such injection injectors, the factors affecting injection, etc., are also the same or substantially the same risks as identified when using parenteral delivery methods, including but not limited to conventional manual hypodermic syringes. Select appropriately to obtain C _max and T _max values of the drug.

The pharmacokinetics of the cytotoxic drug methotrexate are described as specific examples relating to the pharmacokinetics of the dangerous agents disclosed herein.

The pharmacokinetics of injected methotrexate are generally known (e.g. Aquerreta, I., et al., Ped. Blood & Cancer (2003); 42 (1), 52-58; and Seideman, P., et al) , Br. J. Clin. Pharmacol. (1993) April; 35 (4): 409-412). Methotrexate is a weak dicarboxylic acid with an acid dissociation constant of about 4.8 to about 5.5, and is therefore present mostly in ionic form at physiological pH values. After intravenous administration, the initial mean distribution volume of methotrexate is usually about 0.18 L / kg (or about 18% of the subject's weight) and the average steady state distribution volume is usually about 0.4 to 0.8 L / kg (or about 40 to 80 percent of the subject's weight). %)to be. Methotrexate is generally fully absorbed via the parenteral injection route. The peak serum concentration (C _max ) after intramuscular injection of methotrexate reaches within about 30 to 60 minutes (Tmax) in most patients. However, the concentration in the individual plasma of injected methotrexate varies widely from individual to individual. For example, in pediatric patients with combustive rheumatoid arthritis, the mean serum concentration of meporexate is about 0.59 μm per hour (average from about 0.03 μm to 1.40 μm) and about 0.44 μm (2 hours) Averaged in the range of about 0.01 μm to 1.00 μm), and also about 0.29 μm (average in the range of about 0.06 μm to 0.58 μm) at 3 hours. For the treatment of acute lymphocytic leukemia (about 6.3 mg / m 2 to 30 mg / m 2 Dosage) or for pediatric patients injected with methotrexate for the treatment of combustive rheumatoid arthritis (a dose of about 3.75 mg / m 2 to 26.2 mg / m 2), the half-life of methotrexate is about 0.7 to 5.8 hours and 0.9 to Reported over a range of 2.3 hours.

At high doses  Toxicity according to

As seen in many a priori studies, it is uncertain whether the efficacy of the compound will increase when increasing the prescribed dose of methotrexate. However, as methotrexate doses increase, it is clear that toxic side effects also increase. For example, Furst et al. Evaluated the effects of increasing oral methotrexate oral doses from 5 mg / m 2 (7.5 to 10 mg) to 10 mg / m 2 (15 mg to 22 mg) per week (Furst) in 46 patients. , DE, et al., J. Rheumatol., 1989; 16: 313-320). In this study, the authors pointed out that large doses of methotrexate resulted in increased efficacy response with increasing toxicity. However, another study by Lambert et al. Did not confirm that increased methotrexate doses improved efficacy (see Lambert, C.M. et al., Arthritis and Rheumatisim, 2004; 50: 364-371). In this study, the effects of increasing intramuscular methotrexate doses from 15 mg to 45 mg per week were evaluated for 64 patients. The authors observed an improvement in disease activity (DAS) in some patients after a change from oral to intramuscular administration at 15 mg per week (average DAS28 decreased from 5.6 to 5.2). 54 patients who did not achieve good DAS28 values (DAS28 <3.2) showed no significant difference in the improvement of disease compared to placebo-treated patients.

Visser and van der Heijde conducted a number of studies focusing on the efficacy of varying the dosage and mode of administration of methotrexate to subjects with rheumatoid arthritis (Visser, K., and van der Heijde, D., Annal. Rheum. Diseases, 2008; published online 25 November 2008 as doi; 10.1136 / ard. 2008.092668). The authors began by oral administration of methotrexate to the subject in an amount of 15 mg / week, then gradually increased to a dose of 5 mg / month so that the peak concentration reached about 25-30 mg (or the highest tolerated dose) per week and Subsequently, when the response was not sufficient, it was determined that the change to subcutaneous administration was the optimal dose and route of administration of methotrexate for rheumatoid arthritis.

Changes in Bioavailability with Oral Dosage

Many studies have demonstrated that the bioavailability of methotrexate upon oral administration is highly variable. There is evidence suggesting that oral bioavailability of methotrexate is attenuated with increasing dose. For example, Herman et al. Has characterized the bioavailability of intravenous and oral administration of methotrexate at a dose of 10 mg / m2 per week in 41 patients with rheumatoid arthritis (Herman, RA, et al., J. Pharm. Sci., 1989; 78: 165-171). The authors found that the absorption of orally administered methotrexate was only 70% ± 27% of the total absorption observed when the same amount was administered intravenously. Hamilton et al also compared intramuscularly administered methotrexite versus oral administration in 21 patients with rheumatoid arthritis at an initial dose of 7.5 mg per week and an average maintenance dose of 17 mg per week (Hamilton, RA, and Kremer, JM). , Br. J. Rheum., 1997; 36: 86-90). The authors found that the total absorption of metatrexate after oral administration decreased about 13.5% during the maintenance of the dose relative to the total absorption seen at the initial dose.

Kurnik et al. Compared the bioavailability with oral doses of methotrexate of 15 mg to 25 mg in patients with Crohn's disease compared with subcutaneous administration of the same amount (Kurnik, D., et al., Alimentary Pharm. Ther., 2003; 18: 57-63). The authors observed a wide range of changes in oral bioavailability in orally administered patients, with an average bioavailability of about 73% of the total bioavailability found in subcutaneously administered methotrexate.

Hoekstra et al. Evaluated bioavailability at oral and subcutaneous methotrexate doses of 25 mg or more in patients with rheumatoid arthritis (see Hoekstra, M. et al., J. Rheum., 2004; 31: 645-8). . They reported that oral utilization was only 64% of the values found in methotrexate administered subcutaneously at 30 mg / week midweek dose. Relative absorption rates varied from 21 to 96% in tested patients.

Brooks et al. Compared the pharmacokinetics and bioavailability of intramuscular versus subcutaneously administered methotrexate at a dose of 12.5 mg to 25 mg per week (Brooks, PJ et al., Arthritis and Rheumatism, 1990; 33: 91-94 Reference). The authors found similar peak serum concentrations and bioavailability in both routes, but T _max was found to be faster after subcutaneous administration in 4 of 5 patients.

Oguey et al. Evaluated the effect of food on the bioavailability of a 15 mg oral methotrexate in 10 patients with rheumatoid arthritis (see Oguey, D., et al., Arthritis ad Rheumatism, 1992; 35: 611-614). ). They reported that oral bioavailability of 67% and 63%, respectively, under fast feeding conditions was unaffected by food, but pointed out to be in the range of 28 to 94% due to the high intervariability between patients.

Hoekstra et al. Evaluated the effects of a 25-35 mg methotrexate oral dose divided into 8 h intervals in 10 patients with rheumatoid arthritis (Hoekstra, M., et al., J. Rheum). , 2006; 33: 481-485). They found that the bioavailability of the first divided dose increased to 90% of the value achieved in parenteral administration, which is much higher than the 76% bioavailability of the same dose once orally.

Oral vs. Subcutaneous

Recently, Braun et al., A six-month, double-blind, controlled trial of 375 acute rheumatoid arthritis patients comparing clinical efficacy and safety in oral versus subcutaneous methotrexate at an initial dose of 15 mg per week. (Braun, J. et al., Arthritis and Rheumatism, 2008; 58: 73-81). After 16 weeks, most patients who started subcutaneous methotrexate administration successfully achieved the American Rheumatology Association Criteria for 20% improvement (ACR20) over subjects who started oral methotrexate administration. In particular, only 85% of patients who started with subcutaneous methotrexate achieved ACR20, while only 77% of patients started with oral methotrexate.

An increase in ACR20 and the American Rheumatology Association criteria for 70% improvement (ACR70) was also observed after 24 weeks. After 24 weeks, the proportion of patients with the ACR20 response was much higher in the subcutaneous methotrexate group (78%) than the orally administered methotrexate group (70%). In addition, the proportion of patients who achieved a 24-week ACR70 response was higher in patients receiving subcutaneous methotrexate than in patients receiving oral methotrexate (41% vs. 33%).

At week 24, the number of subjects with swollen joints in the group receiving subcutaneous methotrexate was less than in the group receiving oral methotrexate, for example, the number of fragile joints was 3.5 to 6. The median health assessment questionnaire (HAQ) score is an appropriate method of measuring outcome among patients with a wide range of rheumatoid diseases, which was lower in the subcutaneous methotrexate group compared to the oral dose group at week 24 ( 0.4 vs. 0.5). Median disease activity (DAS28) is also an index for measuring disease activity among patients with rheumatoid arthritis, which was also lower than the subcutaneous methotrexate group compared to oral administration group after 24 weeks (3.3 vs. 3.7).

At week 16, only 52 patients (14% of total subjects) were classified as ACR20 non-responders. However, when these patients were changed from 15 mg oral administration to 15 mg subcutaneous administration, 30% of them increased the positive ACR20 response and, among them, the dose of methotrexate administered subcutaneously from 15 mg to 20 mg, again. More than 23% had a positive ACR20 response.

Among subgroup patients with at least one year between diagnosis and study entry prior to receiving disease-regulated antirheumatic compounds or steroids (n = 98), methotrexate oral (63%) and subcutaneous (89%) groups Differences in ACR20 responder ratios were higher than in the total study participants. In addition, in this patient group, the time to achieve an ACR20 response was shorter for 2 weeks in methotrexate subcutaneous administration (4 weeks) than oral administration of methotrexate (6 weeks).

The authors concluded that superior clinical efficacy was demonstrated in subjects who received subcutaneous administration of methotrexate over the same oral dose. In addition, subcutaneous administration did not involve a serious incidence of adverse events.

Oral vs. Intramuscular Administration

Wegrzyn et al. Compared the resistance and efficacy of methotrexate in oral versus intramuscular administration in a study of 143 patients with rheumatoid arthritis (Wegrzyn, J et al., Annal. Rheum. Diseas., 2004; 63: 1232 -1234). In this study, the patient first received methotrexate for intramuscular administration, but later discontinued the supply for about 3 months during the study and then switched to oral administration. 47 patients were then switched back to methotrexate intramuscular administration and observed for 3 months.

After switching to oral administration methotrexate, 49% to 71% of patients reported worsening symptoms (morning and joint pain) and 48% reported nausea. In the group changed to intramuscular administration methotrexate, 40-70% of patients reported symptom improvement (morning pain and joint pain). Some patients (40%) reported nausea. Hepatic transaminase (aminotransferase) increased in about 25% of patients after the change to oral methotrexate and the rate decreased with a subsequent return to muscle methotrexate.

Hoffimeister released a survey over 15 years after the initial supply of methotrexate to 78 patients with rheumatoid arthritis. In this study, patients were given about 10-15 mg of intramuscular mettrexate once a week (Hoffimeister, R.T., Amer. J. Med., 1983; 75 (6A): 69-73). 82% were determined to show moderate or pronounced improvement after treatment. Patients who achieved the expected maximum effect could change to oral methotrexate. Of the 48 patients who changed to oral methotrexate, 10 deteriorated after the change and improved only after returning to intramuscular administration.

Taken together, these pharmacokinetic studies suggest that the better the uptake of maternal methotrexate, the greater the efficacy and resistance compared to the oral dose given.

In some embodiments, one or more of the dangerous agents disclosed herein can be injected within 5 seconds to a depth of about 2 mm to about 10 mm in the subject's tissue using a powered injector according to the present disclosure. In some embodiments, injection can be made to a depth of about 3 mm to about 5 mm, and in some embodiments to a depth of about 3.5 mm. In certain embodiments, a dangerous agent disclosed herein can be injected into a subject's tissue at a pressure of about 200 psi to about 500 psi using a powered injector, in certain embodiments about 300 psi, in some embodiments About 400 psi And in some embodiments about 500 p.s.i. Can be injected under pressure. In some embodiments, the powered injector is needle mounted and in some embodiments the powered injector is needleless. In certain embodiments, the powered injector is a needle-mounted injector, and in some embodiments the powered injector is a needle-free injector.

In certain embodiments, the injectable injector is configured to provide pharmacokinetics of a dangerous agent, such as methotrexate, and includes, without limitation, no effect or substantially impact, unlike parenteral delivery methods, including injection with conventional manual subcutaneous syringes. Not crazy In some embodiments, the spray injector maintains the rate at which the dangerous agent is absorbed into the subject's blood stream, for example by selecting factors that can affect pharmacokinetics, and also injects the dangerous agent using a conventional manual hypodermic syringe. And is adapted to be absorbed into the subject's blood stream at substantially the same rate as, thus maintaining the pharmacokinetics and / or bioavailability of the dangerous agent.

In some embodiments, the injection depth of the dangerous agent may be appropriately modified to deliver the dangerous agent to a subject in a manner that is generally close to the known and / or desired pharmacokinetics of the dangerous agent. In certain embodiments, the depth of injection is increased to maintain the known and / or desired pharmacokinetics of the dangerous agent. In certain embodiments, the depth of injection is reduced to maintain the known and / or desired pharmacokinetics of the dangerous agent. In certain embodiments, the pressure applied to the jet injector may be appropriately modified to deliver the dangerous drug from the jet injector to the subject in a manner that is generally close to the known and / or desired pharmacokinetics of the dangerous drug. In some embodiments, the pressure is increased to maintain the known and / or desired pharmacokinetics of the dangerous agent. In some embodiments, the pressure is reduced to maintain the pharmacokinetics of known and / or desired dangerous agents. Injectable properties aimed at maintaining the known and / or desired pharmacokinetics of the risk agent depend, at least in part, on the nature of the disease of the subject being treated, the nature of the individual subject and the nature of the risk agent to be injected and are known in the art. This can be determined through technology.

In some embodiments, appropriately varying the injection depth such that the pharmacokinetics of methotrexate are the same or substantially the same as the pharmacokinetics of methotrexate administered via parenteral delivery methods, including but not limited to conventional manual subcutaneous syringes. As such, a predetermined dose of methotrexate is delivered from the jet injector to the subject. In some embodiments, appropriately altering the injection pressure such that the pharmacokinetics of methotrexate are the same or substantially the same as the pharmacokinetics of methotrexate administered via parenteral delivery methods, including but not limited to conventional manual subcutaneous syringes. As such, a predetermined dose of methotrexate is delivered from the jet injector to the subject. In some embodiments, the pharmacokinetics of methotrexate may be the same or substantially the same as the pharmacokinetics of methotrexate administered via parenteral delivery methods, including but not limited to conventional manual subcutaneous syringes, by appropriately varying the injection depth and injection pressure. In such a manner, a predetermined dose of methotrexate is delivered from the spray injector to the subject.

 Therapeutic uses

The risk agents of the present invention include patients, in particular in some embodiments humans, and in particular but not limited to cancer, rheumatoid arthritis, combustor rheumatoid arthritis, psoriatic arthritis, systemic lupus erythema, steroid resistant polymyositis or dermatitis, The risk agents of the present invention can be administered to patients suffering from a number of diseases or disorders known, judged or determined later, including Wegner's granulomatosis, nodular polyarthritis, vasculitis, and the like. In certain embodiments, the risk agents of the present invention can be used to treat rheumatoid arthritis.

The suitability of a risk agent provided herein in treating the above-mentioned diseases can be determined according to known methods.

Dose

The amount of risk agent effective for the treatment of a particular disease described above, at least in part, depends on the nature of the disease and can also be determined through standard techniques known in the art. In addition, in vitro or in vivo analysis can help define the appropriate dosage range. Dosage regimens and dosing intervals may also be determined according to methods known in the art. The amount of risk agent administered may depend, among other factors, on the subject being treated, the subject's weight, the severity of the disease, the route of administration and the discretion of the prescribing physician.

In the case of systemic (systemic) administration, the therapeutically effective amount of a risk agent may first be estimated through in vitro analysis. Initial dosages can also be estimated using techniques in the art from in vivo data, such as animal models and the like. This information can be used to more accurately determine useful doses for humans. Those skilled in the art will be able to optimally administer to humans based on animal experimental data.

The dosage of the drug contained in the injector of the dangerous drug, usually a single-feed initial dose, which is pre-filled, is selected so that the dangerous drug of the equivalent molar amount or the mass equivalent dose can be supplied. Dosages may include multiple dosage forms. For example, a therapeutically effective amount of methotrexate for a patient ranges from about 7.5 mg to about 150 mg per 1 ml injection. In certain embodiments, the therapeutically effective amount has a concentration of methotrexate of 15 mg to 75 mg per ml, in certain embodiments 15 mg to 50 mg per ml, and in certain embodiments 15 mg to 25 mg. In some embodiments, the therapeutically effective amount of methotrexate is about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / Ml, about 36 mg / ml, about 37 mg / ml, about 38 mg / ml, about 39 mg / ml, about 40 mg / ml, about 41 mg / ml, about 42 mg / ml, about 43 mg / ml , About 44 mg / ml, about 45 mg / ml, about 46 mg / ml, about 47 mg / ml, about 48 mg / ml, about 49 mg / ml, about 50 mg / ml, about 51 mg / ml, about 52 mg / ml, about 53 mg / ml, about 54 mg / ml, about 55 mg / ml, about 56 mg / ml, about 57 mg / ml, about 58 mg / ml, about 59 mg / ml, about 60 mg / Ml, about 61 mg / ml, about 62 mg / ml, about 63 mg / ml, about 64 mg / ml, about 65 mg / ml, about 70 mg / ml, about 75 mg / ml, about 80 mg / ml , About 85 mg / ml, about 90 mg / ml, about 95 mg / ml, about 100 mg / ml, about 105 mg / ml, about 110 mg / ml, about 115 mg / ml, about 120 mg / ml, about 125 mg / ml, about 130 mg / ml, about 135 mg / ml, about 140 mg / ml, about 145 mg / ml and about 150 mg / ml. The dosage of the dangerous agent and also the appropriate interval of administration can appropriately select a value that allows the dangerous agent in the patient's blood to maintain a therapeutically effective concentration. In certain embodiments the value does not exceed the lowest adverse concentration.

In certain embodiments, the risk agent, including the compound of formula (I), is a pediatric patient with severe rheumatoid arthritis in a selected adult that does not show sufficient response or is unable to tolerate initial treatment with nonsteroidal anti-inflammatory compounds (NSAIDs) or the like. Active multiple combustors of Rheumatoid Arthritis may be administered via injectors to manage. In some embodiments, the dose of a risk agent for adult rheumatoid arthritis is 7.5 mg in a single dose and 2.5 mg in three divided doses at 12 hour intervals. In adult rheumatoid arthritis, the dosage can be adjusted gradually until the optimal response is achieved. However, the risk agent is used at a dose of up to 25 mg at the highest injection route described above.

In certain embodiments, the dangerous agent provided by the present invention may be administered once a day, twice a day, etc. using the injector of the present invention. In certain embodiments, administration may be at one or more time intervals per day. Administration can be administered alone or in combination with other dangerous agents and can be continued as needed for effective disease treatment. Dosing includes administering one or more dangerous agents disclosed herein to the subject in a rapid delivery manner.

Dosages may be administered in a single injection or multiple injections. If multiple injections are chosen, the amount of dangerous agent contained in each dose may be the same or different.

In certain embodiments, the dosage is less than a toxic dosage. Toxicity of dangerous agents disclosed herein is well known in the art and can be achieved in cell culture or experimental animals, for example, by means of standard pharmaceutical methods, such as LD ₅₀ (the dose causing 50% lethality of the population) or LD ₁₀₀ ( ₁₀₀ of the population). Can be determined by determining the dose causing the% lethality). The ratio of dose between toxic and therapeutic efficacy is called the therapeutic index. In certain embodiments, the risk agent exhibits a high therapeutic index. Data obtained in the art, cell culture assays, and data obtained as a result of animal studies can be used to define dosage ranges that are not toxic to human use. The dosage of the harmful compound is a range of circulating concentrations, preferably a range of circulating concentrations in blood, plasma or the central nervous system, etc., which is therapeutically effective and shows little or no toxicity.

Dosages and dosing schedules during treatment impart sufficient or steady state total concentrations of one or more dangerous agents. In certain embodiments, administration may be by increasing the dosage.

When administered through the powered injector of the present invention, the dangerous agent of the present invention, if the medical professional is to be injected directly to the patient, oral dosage form to be administered several times per week, and the prescription which is inconvenient or difficult to remember for the patient As such, non-clinical administration of harmful drugs through self-administration of the patient is possible, thereby improving patient compliance. Compliance will also be further improved because the rate at which the powered injector herein delivers the dangerous agent to the injection site is within about 5 seconds. In addition, the powered injectors herein can deliver dangerous agents more precisely, in a controlled delivery manner, thereby reducing the risk of exposing the dangerous agent out of the injection site and, in certain embodiments, can completely eliminate the risk of exposure. In some embodiments, the injector is prefilled with one or more dangerous agents so that the user does not have to extract it directly. Otherwise, the above operation is required as with a conventional manual syringe. Therefore, in the administration of dangerous drugs, in particular, it is possible to work and precise administration to patients who are suffering from a disease or a disease and directly extract the drugs and inject them themselves. Therefore, administration of a dangerous agent of the present invention via the powered injector herein provides a safe delivery means, significantly reduces the risk of exposure of the dangerous injector to a dangerous drug, and also provides a patient with a powered injector. This reduces the risk of unnecessary toxicity.

As disclosed herein, the administration of a dangerous agent is determined that the patient and currently available product specifications that would benefit from switching the oral dosage form of the dangerous agent to an injectable dosage form of the same drug are not practical for performing self-injection. It can be a new alternative for all your doctors. These include, but are not limited to, compounds of formula (I). In addition, the administration of the dangerous agent through the powered injector of the present application is expected to increase the simplicity and ease in use by a patient with a physical disability, such as rheumatoid arthritis. In addition, the administration of a dangerous drug through the powered injector herein can reduce the overall number of health care costs by reducing the overall number of visits to medical personnel for drug injection.

In certain embodiments, the dangerous agent can be self-administered by the subject within 5 seconds via the needle-mounted powered injector herein. The use of powered injectors makes it easier for the subject to self-administer, increase concentrations in the delivery of dangerous drugs, and reduce the toxic risks associated with dangerous drugs, resulting in the treatment of chronic diseases such as rheumatoid arthritis. I believe it will be more widely available. In addition, such injectors have increased concentrations by fully delivering the dose to be administered to the patient, while reducing the risk of losing the dangerous drug out of the injection site and also reducing the toxic risk associated with dangerous drug injection, thereby reducing the risk agent for the patient. It is expected that the clinical use of the drug may be improved. Thus, the overall patient's compliance will be improved and the likelihood of administering a dangerous agent for therapeutic use will also be increased prior to switching to a biological product which is a regular clinical procedure.

Injector

Conventional hypodermic syringes perform injections using the pressing force of one or more fingers of a user. In some embodiments, the powered injector of the present invention is configured to help repeatedly and rapidly administer one or more dangerous agents to a subject at a predetermined depth for each injection within about 5 seconds, without the need to use such a press force. .

Auto-injector implementations of known powered injectors use an energy source that makes adjustments at low pressure in the drug chamber such that the drug contained in the drug chamber is launched at low speed, similar to the pressure and speed from the finger driven injector. On the other hand, the autoinjector embodiment of the powered injector of the present invention uses an energy source that makes adjustments at high speed in the drug chamber such that the drug contained in the drug chamber is launched at high speed and is completely injected into the subject within about 5 seconds. . Another embodiment of a powered injector is a jet injector, which may be a needle mounted or a needleless injector. Injection injector embodiments may be configured to have an energy source selected to produce a high pressure in the drug chamber to release the drug at sufficient pressure, force, and speed to leave the injector such as a fluid injection. As described in more detail below, drugs injected to a subject via an autoinjector or a hypodermic syringe are delivered near the tip of the needle as droplets, and the drug delivered from the jet injector is quickly delivered to the tissue, typically away from the tip of the needle. In this case, the drug typically will not accumulate droplets in the needle tip region. Needleless injectors use sufficient pressure and injection speeds to allow fluid jets to penetrate through the outer layers of the skin and place drugs under them. Needle-mounted injectors can use lower pressure than needleless injectors because they employ a needle to penetrate through the outer part of the skin, but with a sufficiently high pressure and speed the drug leaves the needle tip as a fluid jet .

Some embodiments of the injectors disclosed herein are single-shot injectors configured to deliver in a single volume the total volume of medicament (s) contained within the chamber of the injector or in a cartridge contained within the injector. In another embodiment, the injector is configured to inject only a portion of the injector or the contents of the cartridge in the injector, and may use a dose setting device that allows selection of the volume of injection to be delivered in a single shot, or other device that provides an adjustable dosage. In each of the embodiments described above, the injector may be prefilled or may be configured to receive a cartridge having a dosage of drug. Another embodiment is configured to be chargeable as is known in the art.

The injector provided by the present invention can be used by a patient to inject one or more dangerous agents by themselves. Various aspects of the invention relate to a patient self-injecting one or more dangerous agents without the assistance of a health care provider. In certain embodiments, the injector uses a needle to inject a dangerous agent into a patient's target tissue, such as an autoinjector or a needle-mounted injector injector embodiment, while another embodiment is a needleless injector and thus the subject's target No needle is required to inject the dangerous agent into the tissue. In certain embodiments, the injector may utilize sufficient pressure to deliver one or more dangerous agents completely and quickly. In certain embodiments, the injector can utilize a pressure that is high enough to deliver one or more dangerous agents to the fluid jet stream completely and quickly.

In some embodiments, the powered injectors provided by the present invention do not require any first or preparatory step to place them in the state of delivering the injection, such that dangerous agents from the needle of the injector may be released into the air prior to delivery firing. Reduce or eliminate the exposure or premature release of dangerous drugs. Therefore, the risk of the subject or non-user of the injector coming into contact with the dangerous agent contained in the injector is reduced or eliminated.

1 to 5, an embodiment of the injector according to the invention is shown. The embodiment shown in these figures is a needle injector and may comprise an autoinjector or a needle-mounted injector, depending on the spring and delivery tube used, including the needle and the injection outlet. The injector 12 shown has an outer housing member 14 configured to allow a user to handle the injector 12 and to substantially receive most of the components shown in FIG. 2. In some embodiments, the outer housing 14 is formed of two mating portions 14a, 14b that can be configured to be joined to each other by snap or pressure assembly, or using adhesives, welding, or the like. The housing 14 has a fluid chamber 22 therein configured to store and administer one or more liquid drugs, such as one or more dangerous drugs. In the embodiment shown in FIG. 2, the fluid chamber 22 is formed of a prefilled syringe 18 that is assembled within the housing 14, but other types of fluids, including cartridges of known type that can be prefilled or refilled. Chamber, or drug (s) can be used. In addition, the fluid chamber 22 may be integrally formed in the housing 14.

In the illustrated embodiment, the safety member 80 is disposed at the proximal end of the outer housing 14, ie at the top end of the housing, which is external to form a press assembly between the safety member 80 and the outer housing 14. Removably attached thereto by a plurality of tabs extending through the mating openings formed in the housing 14. The safety member 80 is configured to prevent or reduce the likelihood of inadvertent firing of the injection device, for example during the transport or handling of the injector 12. The safety member 80 can be removed by the user of the injector 12 to allow unrestricted use of the injector 12. Another embodiment of the injector can be configured without the safety member 80.

In a further embodiment, the sleeve 16 is received in or mounted to the housing 14 to act as a syringe support member. In some embodiments, the sleeve 16 holds a prefilled syringe 18, a carpule or other container of the type known in the art, such as, for example, a BD Hypak ^™ prefilled syringe (Becton, Dickinson and Company). And to position. One example of a suitable prefilled syringe for use in the illustrated embodiment is one available in a variety of sizes and volumes, such as Becton Dickinson Hypak ^™ , and commercially available prefilled with drugs. In some embodiments, the glass of the syringe body may be attached to the needle. The use of prefilled syringes facilitates the handling of drugs in the assembly of the injector, and has become a widespread substance of knowledge about how to maintain and act on the drugs in the prefilled syringes. In some embodiments, the sleeve 16 is substantially secured to the housing 12 by snaps, adhesives, welding, or other known attachments. The prefilled syringe 18 may have a container portion 20 defined inside the fluid chamber 22, which is filled with injectable drugs, such as one or more dangerous agents. In other embodiments, for example, the drug container and chamber are provided by another structure, such as a chamber that can be integrated with or maintained in the housing, needle hub 32, or other injection outlet of the injector. At the end of the prefilled syringe 18 is an injection support needle 24. This needle 24 has an injection tip 26 configured as known in the art to penetrate the tissue of a patient who is in some embodiments skin. The needle hole extends through the needle 24, as is known in the art. This hole is in fluid communication with the drug in the fluid chamber 22 and is open at the needle tip 26 to inject the drug.

At the tip of the fluid chamber 22 is a plunger 28 that seals the drug in the fluid chamber 22 opposite the needle 24. In some embodiments, the syringe wall includes a tubular portion, in some embodiments, which is closed at the distal end and open at the tip, and defines the fluid chamber 22. The plunger 28 is slidably accommodated in the tubular portion. The prefilled syringe 18 is configured to reduce the volume of the fluid chamber 22 as the plunger 28 moves in the distal direction, thereby pushing the drug out of the chamber 22 through the hole in the needle 24. At the end of the fluid chamber 22 is a needle hub 32 on which a needle is mounted. The syringe flange 35 extends radially from the end of the syringe wall. In an injector embodiment using a cartridge, a carpool or another container providing a chamber for containing a drug, the needle is connected directly to a cartridge, carpool, or other container, or to another part of the injector such as its housing, or a separate The needle hub may be in fluid communication with the chamber in various ways.

In the embodiment shown in FIG. 2, the prefilled syringe 18 has a syringe body 36, and the flange 35, syringe wall, and hub portion 32 are in a unitary configuration. In some embodiments, the material comprising the syringe body 36 is glass, but other embodiments may use other materials, such as plastic or metal, for example.

To radially position the distal end of the prefilled syringe 18, in some embodiments the sleeve 16 has a narrow hole 51 that can be configured to be adjacent to the outside of the syringe wall. This is particularly beneficial when the needle is inserted into the patient's skin. The narrow bore 51 may be made of an elastic material, such as an elastomer, or may be made integrally with the remainder of the sleeve 16 by a series of radially arranged elastic flexible fingers or the like. In addition, the tip of the syringe 18 may be held in place by the shock absorber 33, and in some embodiments the tip is radially located on the tip side of the syringe body 36 to provide an injection injector embodiment. As such, it absorbs the impact from the impact of the sudden firing of the pressurization ram 60, which creates an upward pressure in the fluid chamber 22 or the vessel 20.

The trigger mechanism may also be housed in the housing 14. In some embodiments, the trigger mechanism has an inner housing 54 that can be attached to the outer housing 14 by snaps, adhesives, welding, or other known attachments. The trigger protrusion 56 extends inward from the tip of the inner housing 54 and is elastically pressed outward. The trigger protrusion 56 is received in the recess 58 of the pressure rod 60 in blocking engagement therewith to prevent distal movement of the pressure rod 60 prior to the launch of the device. The pressure rod 60 may in some embodiments use other suitable energy sources, such as elastomers, compressed gas springs, or gas generators, but in some embodiments may be applied to the injector 10 by means of an energy source, which is a compression spring 52. Displaced towards the distal end. One example of a compression spring 52 for proper use with the injector of the present invention is a coil spring. Other embodiments may use other suitable trigger mechanisms as known in the art.

A latch housing 64 is provided on the outer surface of the inner housing 54 to hold the pressure bar 60 in the distal position until the firing is activated to retain the trigger protrusion 56 in the recess 58. Can be. The latch 64 is slidable with respect to the inner housing 54 in some embodiments axially in the interior of the outer housing 14, and in some embodiments the latch 64 wraps the inner housing 54. In some embodiments the latch 64 is free to move relative to the outer housing 14 and, after removal of the safety member 80, is fixed in place only by the pressure exerted thereon by the trigger protrusion 56. In some aspects, there is no pressing of the latch housing 64 away from the tip of the outer housing 14, including a spring or the like. Other embodiments may use drug containers that come forward when the device is operated to pierce the skin with a needle, and some embodiments may be operated by buttons on the side of the housing, or other parts of the injector, at the distal end. Use a handle mechanism.

The housing 14 may have a needle guard 66 that can move relative to the outer housing 14. In the embodiment of the needle protector 66 shown in FIG. 2, the needle protector 66 is in the protruding position, with the needle 24 disposed in the protector 66. The protrusion (65 in FIG. 8) is adjacent to the inner surface of the outer housing 14 to hold the needle protector 66 in the housing 14 when the needle protector 66 fully extends to the protruding position. The needle guard 66 may retract in the outer housing 14 in a direction proximate to the injection position in some embodiments, with the tip of the needle tip 26 and the tip 24 being inserted into the patient in FIG. 6B. And as shown at 6C. In some embodiments, tip movement of the protector 66 is impeded at the injection position.

The needle guard 66 may be engaged with the latch 64 so that when the guard 66 moves to the tip it slides the latch 64 in the tip direction so that the trigger protrusion 56 is released from the recess 58. have. In some embodiments, the latch 64 is coupled to pressurize and retain the trigger protrusion 58 positioned in blocking engagement with the push rod 60 prior to firing of the injector 12, adjacent to the inner housing 54. Has a locking portion 68. In some embodiments, when the latch 64 slides close to the injection position by the retraction of the guard 66, the lock 68 moves away from the recess 58 of the pressure rod 60. By sliding past the portion of the inner housing 54 that contacts and bends, the trigger protrusion 56 allows it to move radially outward from the recess 58 and thus from the blocking engagement. When this occurs, the spring 52 presses the pressure rod 60 against the plunger 28 to launch the injector 12.

In some embodiments, securing the cap 110 to the distal end of the injector 12 may cover the needle guard 66 and prevent its accidental movement during transportation or during handling prior to injection. The cap can be fixed to the end of the outer housing 14 by press coupling, screwing, or the like. In certain embodiments, the cap 110 may have a pair of protrusions extending inwardly (FIG. 9), the protrusions forming distal opposing protrusions 114. In such an embodiment, the needle guard 66 is a pair of radially extending flanges (67 of FIG. 8) configured to abut the distal protrusion 114 of the protrusion 112 to secure the cap 110 to the injector 12. ) Can be configured. In some embodiments, the upper edge of the cap 110 (116 of FIG. 9) is adjacent to the distal end of the outer housing 14 such that the distal edge 114 of the protrusion 112 can be held relative to the flange 67. . This arrangement of the cap 110 prevents the needle guard 66 from compressing close to the housing as the cap 110 is placed side by side between the guard 66 and the housing, and the needle guard 66 is in a protective position. To help prevent accidental firing of the injection device.

In some embodiments, twisting the cap 110 relative to the housing 14 may cause the protrusion 112 to move out of alignment with the flange 67 to remove the cap 110 from the injector 12, thereby causing ( It is possible for 110 to be distal from the needle guard 66 to the end. To prevent inadvertent removal of the cap 110 from the injector 12 due to inadvertent rotation of the cap 110, in some embodiments, prior to completing the rotation, for example to remove the cap 110, its closed The cap 110 is required to click away from the position. As such, the cap 110 is coupled to the housing 14 or needle guard 66 so that a large force is initially required. For example, the upper edge 116 of the cap 110 can be inclined, as shown in FIG. 9. The slope may include a curve as shown, but generally the edge 116 may have one edge 118 higher than the other edge 120. In some embodiments, the distal end of the outer housing 14 can have a profile that coincides with the distal end of the upper rim 118 of the cap 110. This arrangement requires displacement of the cap 110 to allow for rotation of the cap and to increase the force necessary for the cap 110 to cause rotation relative to the needle guard 66. In other embodiments, the cap 110 may have a threaded or cam-type engagement with the flange 67 or may have a different arrangement so that the cap 110 is removed by rotation.

Cap 110 may be attached to injector 12 during its assembly. This can be done by properly aligning the cap 110 and rotating it relative to the needle guard 66 while applying a direct force in the tip direction to the cap 112 to move back beyond the flange 67. In addition, the flanges 67 can be configured to be deformable inward by placing them in the corresponding tabs 69 formed on the needle guard 66. In such an embodiment, the cap 110 may be assembled on the needle guard 66 prior to assembling the spring 72 therein, which may interfere with the inner deformation of the flange 67. In addition, cap 110 may be elastically deformed to press on needle guard 66 such that protrusion 112 passes over flange 67.

In some implementations, the needle guard 66 can be elastically urged to the distal end towards the protected position by the compression coil spring 72. In addition, the needle guard 66 may have an axial opening 74 that allows the needle 24 to pass through, which may be sized to correspond to the shape of the desired injector. In some embodiments, the configuration of the injector 12 allows the user to press the end of the injector 12 against the patient's skin, with the needle 24 at about the same speed as the injector 12 entering the skin. Into the skin from the insertion position. Once the needle 24 is fully inserted to the insertion point at the desired penetration depth, the trigger mechanism is launched to inject the drug into the injection site.

In some embodiments, for subcutaneous injection using, for example, a needle mounted jet injector, the needle guard 66 may be configured to allow the needle 24 to be inserted to a depth of skin penetration that is up to about 5 mm below the skin surface. have. In some embodiments, the penetration depth is within about 4 mm and in some embodiments within about 3 mm. In some embodiments, the insertion depth is at least about 0.5 mm, and in some embodiments at least about 1 mm. In other embodiments, the length of the needle tip 26 extending beyond the distal end of the needle guard 66 or the needle guard 66 in contact with the skin is at most about 5 mm, in some embodiments at most about 4 mm, some In an embodiment up to about 3 mm. In some embodiments, the extension length is at least about 0.5 mm, in some embodiments at least about 1 mm, and in some embodiments at least about 2 mm. In some embodiments, the needle tip 26 extends beyond the needle guard 66 at a distance of about 2.5 mm or more beyond the portion of the needle guard 66 that contacts the skin at the injection position.

In another embodiment, for intramuscular injection using, for example, a needle-mounted jet injector, the injector 12 is a needle guard 66 with a length of up to about 15 mm, or up to a depth of penetration of the needle 24 into the patient's skin. It can be configured to allow insertion beyond the end face of the). In some embodiments, this length can be from about 10 mm to about 14 mm. In some embodiments, the penetration depth of needle tip 26 or the length beyond needle guard 66 may be between about 12 mm and about 13.5 mm, and in some embodiments may be about 12.7 mm. Other exposed needle 24 lengths may be selected for jet injection to different depths below the skin, with an overall penetration length of about 0.5 mm to about 20 mm. In these embodiments, the needle guard 66 may be configured to retract from the protruding position and, in some embodiments, cover the entire needle to the injection position. In the injection position, the desired length of the tip 26 of the needle 24 is exposed.

The safety member 80 is detachably secured to the distal end of the outer housing 14 and has a body portion 84 and a pair of elastically flexible legs 82 extending therefrom (FIGS. 4A and 4B). The leg 82 is configured to extend into a corresponding hole or slot 15 formed in the distal end of the outer housing 14 and is press-coupled within the slot 15 to hold the safety member 80 on the housing 14. Can be made to provide The leg 82 may be pushed outward and further includes a tab 86 disposed on its outer surface, so that the position of the slot 15 for additional retention of the safety member 80 on the outer housing 14. Can be coupled to the inside of the outer housing (14). In some implementations, the leg 82 can be made to allow the user to remove the safety member 80 from the outer housing 14 when an injection is desired. However, in some embodiments, the leg 82 prevents it from being accidentally or inadvertently removed from its position attached to the outer housing 14.

The leg 82, when properly attached to the outer housing 14 in the tip direction, is adjacent to the top end surface of the locking part 64 (FIG. 3), so that the locking part in the tip direction, which may cause the injection of the injection mechanism, may occur. Interfere with or block jungle or other movements of (64). In some embodiments, the leg 82 is configured to be associated with the trigger mechanism of the housing 14 and the injector 12, thereby providing the necessary force against the lock 64 to move the leg 82 out of the slot 15. The silver is sufficient to prevent the locking portion 64 from being pushed out of position due to severe shock during transportation or handling caused by vibration during transportation or dropping of the injector 12. Other safety members may be used to prevent inadvertent firing of the injector 12.

In embodiments where the injector 12 consists of a needle-mounted injector, the spring 72 and prefilled syringe 18 may be configured to inject a drug, such as a dangerous agent. Therefore, the spring 72 exerts a force on the plunger 28 which may be sufficient to raise the pressure in the fluid chamber 22 to a high level sufficient to release the drug from the needle 24 as a fluid jet. In many embodiments, the jet injection is drug injection from the needle tip 26 of the injector 12 at a speed and force sufficient to deliver the drug to a location remote from the needle tip 26.

Several injection injector implementations, needle- or needle-less, employ an energy source selected to generate high pressure in the drug chamber 22 to release the drug therefrom at a force and speed sufficient to leave the injector 12 as a fluid jet. Have Jet injectors are believed to inherently "spray" the drug subcutaneously into the subject, thereby rapidly delivering the drug over a larger surface area beneath the subject's skin, thereby rapidly exposing the larger area of the patient's target tissue to the drug.

When delivered by an autoinjector, typically the drug leaves the autoinjector and is locally distributed because it does not fire far from the injection outlet, and therefore is delivered as a droplet near the needle tip of the autoinjector. This is because the autoinjector requires additional injection time to deliver the injection to a resistive medium, such as tissue, as opposed to delivering it into the air. On the other hand, embodiments of the powered injector disclosed herein, and in particular the embodiments of the disclosed injector, show no difference in injection time when scanning into a resistive medium compared to air. Since the drug delivered by the jet injector is rapidly jetted into the patient's tissue essentially away from the needle tip, the drug does not leave the jet injector as a drop or droplet, and thus is not delivered to the subject as a droplet in the needle tip area. Therefore, by using the spray injector disclosed herein, the drug can be dispersed more efficiently into the tissue of the patient. In addition, because the injectable injector delivers the drug at high pressure and high speed, the delivered drug has a lower tendency for the injection liquid to retreat to the area around the needle or injection track and leak. Therefore, the backflow from the depth of the drug is delivered back to the injection site and the backflow to the surface of the subject's skin can be greatly reduced by the use of a jet injector. Therefore, when used to deliver one or more drugs according to the present invention, such as one or more hazardous agents, jet injectors greatly reduce the risk of drug exposure outside the injection site, thereby reducing the overall dosage to the desired depth. While delivering reliably, it reduces the risk of drug exposure to non-users and the subjects themselves. Preventing or reducing reflux is beneficial in improving compliance by ensuring that the drug remains at the injection site at the desired depth. This not only improves the efficiency of delivery, but also avoids drug migration from the injection site to other tissues, layers of tissue, and out of the injection site. Preventing or reducing reflux can be beneficial in maintaining a drug, such as a dangerous agent contained in a single area, thereby preventing the drug from being inadvertently exposed to the surface of the skin from reflux to the subject or another individual near the subject. Such exposure may include, for example, contact with the drug directly on the subject's skin or with micronized drug that can reach the patient or a nearby individual through air or other media. In addition, in many cases, patients using slow injections of a manual hypodermic syringe or autoinjector are at risk of removing the manual syringe from the injection site before the launch is completed, bringing the drug out of the patient's tissue. In some cases, aerosolization of harmful drugs is brought about. This is often due to the long injection time required for injection via a manual hypodermic syringe or autoinjector, which may be in the order of 5, 10 or 15 seconds or sometimes even longer.

In some embodiments, the injector 12 is delivered to the patient or another individual, for example, by jet injection in a manner that prevents or greatly reduces the incidence, reflux, and risk of overexposure of the drug to the air or external surfaces of the patient's skin. It is configured to deliver a drug such as a deleterious dangerous agent and an injection is made.

Table 1 shows the test results compared to the reflux drug reaching the subject's skin surface after injection; Data is shown for a needle-mounted injection injector compared to a manual hypodermic syringe. The total number of injections for each group in the trial was 126, all injected by experienced health care professionals.

Drug backflow to the skin surface after subject injection. % = The total percentage of 126 shots Injection site assessment after injection Needle Mounted Injector Injector and needle -Completely dry area 89 (71%) 76 (60%) Slightly wetted area 36 (29%) 50 (40%) -Measurable moisture but slight (drops) 1 (0%) 0 (0%) Injection site is very wet 0 (0%) 0 (0%)

Since the jet injector delivers the drug quickly within about 2 seconds in some embodiments, the total time of the patient to maintain the injector in the patient's tissue is greatly reduced compared to injection delivered by conventional syringes or autoinjectors. . Therefore, the use of a jet injector according to the invention results in increased patient compliance and compliance with the instructions for use, thus increasing the correct administration of the dosage. In addition, the rate at which the jet injector delivers the drug minimizes the amount of pain experienced in the patient's own drug injection experience, and in many cases pain does not exist, further enhancing patient compliance with regular injections. You can.

Referring to the graph shown in FIG. 10, number 132 represents the time point when the implementation of the injector 12 is fired, and number 134 represents the completion point of the scan. In some embodiments, the injection is complete when plunger 28 hits the end wall of drug container 20. Number 136 represents the initial and peak pressure during the injection, and number 130 represents the final pressure during the injection. In some embodiments, the spring 72 has a linear spring contact and the injection support needle 24 is used to puncture the skin before the start of injection. Therefore, the pressure of the injection drops almost linearly from the beginning of the injection 132 until the injection is complete 134. The final pressure 130 at the completion of the injection 134 rises sufficiently so that even at the end of the firing stroke of the pressure rod 60, the drug is still injected and a very small amount of droplets around the needle tip 26 There is or no drug.

In some embodiments of the needle-mounted injector, the peak pressure 136 during injection is about 1,000 p.s.i. Less than 950 p.s.i. Less than 900 p.s.i. Less than 850 p.s.i. Less than 800 p.s.i. Less than 750 p.s.i. Less than 700 p.s.i. Less than 650 p.s.i. Less than 600 p.s.i. Less than 550 p.s.i. Less than 500 p.s.i. Less than 450 p.s.i. Less than 400 p.s.i. Less than 350 p.s.i. Is less than. In some embodiments, at completion of injection 1080, the pressure 130 applied to the drug in fluid chamber 22 is about 80 p.s.i. As such, in some embodiments, about 90 p.s.i. As such, in some embodiments, about 100 p.s.i. As such, in some embodiments, about 150 p.s.i. As such, in some embodiments, about 200 p.s.i. As such, in some embodiments, about 250 p.s.i. As such, in some embodiments, about 300 p.s.i. As such, in some embodiments, about 350 p.s.i. As such, in some embodiments, about 400 p.s.i. As such, in some embodiments, about 450 p.s.i. As such, in some embodiments, about 500 p.s.i. It may be abnormal. In some embodiments, the initial pressure 136 is about 330 p.s.i. And the final pressure 130 is about 180 p.s.i. to be. In some embodiments the initial pressure 136 is about 300 p.s.i. About 110 p.s.i. at completion of injection (134). Is lowered. In other embodiments disclosed herein, different injection rates are used. For example, a needleless injector may be approximately 4,000 p.s.i. The scanning pressure of the above range can be added. Another embodiment of a jet injector is about 80 p.s.i. Or about 60 p.s.i. As described above, a low injection pressure is used. On the other hand, the known autoinjectors are 60 p.s.i. Use lower pressure.

The needle used in some embodiments of both the autoinjector and the needle mounted injector is 26 to 28 gauge, in some embodiments about 27 gauge. For example, if other components are cooperatively configured to produce the desired injection, including mini needles, other needle gauges may also be used. In some embodiments, components of injector 12 may be configured to spray injection one or more drugs into a subcutaneous injection area.

The amount of drug contained in and injected from the liquid chamber 22 may be from about 0.02 ml to about 4 ml, in some embodiments about 3 ml, and in some embodiments about 1 ml. In addition, larger volumes may be selected depending on the particular drug (s) used and the dosage required. In some embodiments, a prefilled syringe 18 containing a desired amount of drug is assembled to the remainder of the jet injector 12. In some embodiments, prefilled syringe 18 contains about 0.02 ml to about 4.00 ml of one or more drugs. In some embodiments, prefilled syringe 18 contains about 1 ml of one or more drugs.

In embodiments of the needle-mounted injector, the injection rate is less than about 0.75 ml / sec, in some embodiments, about 0.6 ml / sec, in some embodiments, at least about 0.2 ml / sec, in some embodiments, at least about 0.3 ml / sec. Or greater than about 0.4 ml / sec in some embodiments. In some embodiments, the injection rate is less than about 0.75 ml / sec, less than about 0.7 ml / sec, less than about 0.65 ml / sec, less than about 0.6 ml / sec, less than about 0.55 ml / sec, less than about 0.5 ml / sec, Less than about 0.45 ml / sec, less than about 0.4 ml / sec, less than about 0.35 ml / sec, less than about 0.3 ml / sec, less than about 0.25 ml / sec. In some embodiments, the injection rate is at least about 0.2 ml / sec, at least about 0.25 ml / sec, at least about 0.3 ml / sec, at least about 0.35 ml / sec, at least about 0.4 ml / sec, at least about 0.45 ml / sec, At least about 0.5 ml / sec, at least about 0.55 ml / sec, at least about 0.6 ml / sec, at least about 0.65 ml / sec, at least about 0.7 ml / sec. In some embodiments, the total injection amount of the drug is within about 5 seconds, in some embodiments within about 4.5 seconds, in some embodiments within about 4 seconds, in some embodiments within about 3.5 seconds, in some embodiments within about 3 seconds In some embodiments, within about 2.5 seconds, in some embodiments, within about 2 seconds, and in some embodiments, within about 1.5 seconds. In some embodiments, the drug injection is at least about 1 second, in some embodiments at least about 1.5 seconds, in some embodiments at least about 1.75 seconds, in some embodiments at least about 2 seconds, in some embodiments at least about 2.5 seconds, in some In some embodiments, at least about 3 seconds, in some embodiments, at least about 3.5 seconds, in some embodiments, at least about 4 seconds, in some embodiments, at least about 4.5 seconds. In some embodiments, the injection of the drug occurs at about 0.5 ml / second to complete 1 ml of injection in about 1 second. In some embodiments, about 0.5 ml drug injection occurs within about 1 second. In some embodiments, about 1.0 ml drug injection occurs within about 2 seconds. However, other scanning speeds are possible for other embodiments of the injector 12 disclosed herein. For example, in some embodiments injector 12 may be configured to deliver a typical flow rate for needleless injection, which may be about 1.5 ml / sec, and in some embodiments injector 12 for autoinjectors. It can be configured to deliver a normal flow rate, which can be about 0.5 ml in 0.3 seconds.

The rate of injection may, for example, measure the gauge of the needle used to inject the drug, the viscosity of the drug itself, the glide force of the plunger 28 in the syringe barrel, and the temperature of the drug to be injected (the temperature will directly affect the viscosity). Can be affected by a number of factors, such as: In various embodiments, it is also achievable that tissue resistance does not affect the injection rate of the injector embodiments of the present invention. In various aspects, these factors can be selected and optimized to deliver large amounts of injection solution in a desired manner. Such selection and optimization can be readily performed by one of ordinary skill in the art without much experimentation.

In some embodiments, viscous drugs that otherwise require longer injection times can still be injected into the subject at the aforementioned injection rates by changing the gauge of the needle. For example, in some embodiments a 26 gauge needle can be used with the needle-mounted injector of the present invention to inject viscous material, and in some embodiments a 27-gauge with the needle-mounted injector of the present invention can be used to inject viscous material. Needles may be used and in some embodiments 28 gauge needles may be used with the needle-mounted injectors of the present invention to inject viscous material. In each of the above embodiments, the scanning rate is the same as the above-mentioned scanning rate. Therefore, the injection speed can be maintained by changing the gauge of the needle according to the viscosity of the drug to be injected. In some embodiments, the injector of the present invention for delivering 1.0 ml of a liquid solution to air at a duration of about 1.0 to about 2.0 seconds, in some embodiments about 1.5 to about 2.0 seconds, and in some embodiments about 1.7 seconds A 72 gauge needle can be used with one or more embodiments of. In some embodiments, for a duration of about 1.0 to about 2.0 seconds, in some embodiments about 1.3 to about 2.0 seconds, in some embodiments about 1.5 seconds, and in some embodiments about 1.3 seconds, 1.0 ml of liquid solution is added to the air. For delivery, a 72 gauge needle may be used with one or more embodiments of the injectors of the present invention. In some embodiments, from about 1.0 to about 5.0 seconds, in some embodiments from about 2.5 to about 5.0 seconds, in some embodiments about 4.3 seconds, and in some embodiments about 4.0 seconds, 10% w / w polyethylene in water A 72 gauge needle can be used with one or more embodiments of the injectors of the present invention to deliver 1.0 ml of a viscous solution with a viscosity equivalent to glycol 20,000 in the air. In some embodiments, a duration of about 10 to about 15 seconds, in some embodiments about 12 to about 15 seconds, and in some embodiments about 14 seconds, 1.0 having a viscosity equivalent to 20% w / w polyethylene glycol 20,000 in water A 72 gauge needle can be used with one or more embodiments of the injectors of the present invention to deliver ml of viscous solution in air.

The centimeter-gram-second (csg) physical unit for dynamic viscosity is poise (P), which in ASTM standards is more commonly expressed as centipoise (cP). Typically, the liquid solution at 20 ° C. has a viscosity of about 1 cP. In some embodiments, the injectors of the present invention can be configured to produce a flow rate, or injection rate, of 0.5 ml / sec for a liquid solution with 1.0 or near cP through a 27 gauge needle. In some embodiments, the injectors of the present invention can be configured to produce a flow rate of 0.5 ml / sec, or injection rate, into the skin for a liquid solution with 1.0 or close cP through a 27 gauge needle.

U. S. Patent No. 6,391, 003 discloses experimental results of pressure that can be continuously applied to drugs in glass cartridges using 26 and 27 gauge needles. Table 2 shows exemplary injections with different peak pressures that can be used with needle mounted injection injectors, especially when using glass, prefilled syringes.

Exemplary Injection Deliverable with a Needle Mounted Injector Pressure and time (in seconds) for 1 cc injection pressure 26 gauge needle 27 gauge needle 150 p.s.i. 2.1 4.2 200 p.s.i. 1.9 3.9 240 p.s.i. 1.7 3.3 375 p.s.i. 1.4 3.1

It is not always possible to achieve jet injection with the proper dispersion at the desired depth, substantially without reflux of the drug, but it is not always possible to use higher pressures and flow rates as the needle penetration into the patient's skin is shorter. Sleep will recognize. Other embodiments may use higher or lower injection pressures. For example, needleless injectors can use higher pressures to penetrate the skin without needles, and autoinjectors typically use lower pressures to facilitate injection of a manual syringe.

In some embodiments of a needle-mounted injector, in some embodiments without any backflow, short needles can be used to inject drugs into different parts of the skin. A needle 24 extending about 2.5 mm beyond the distal end of the needle guard 66, a 27 gauge needle 24, and a fluid peaking at about 300 psi and completed at about 100 psi and resulting in a flow rate of about 0.5 ml / sec. Using the pressure in chamber 22, 1 ml of drug was run continuously without significant backflow at about 100% of the test injection, as shown in Table 1, slightly or measurable, but still only traces of wetness were observed at the injection site. Can be injected. Therefore, the needle-mounted jet injectors of the present invention allow injection injection of one or more drugs reliably using very short needles, despite the skin thickness, age, weight or other factors of the patient.

In some embodiments, the selection of the spring type as the power source, the adjustment of the force delivered by the spring, and the manner in which the spring is embedded in the assembled injector, result in a significant reduction in the time required to completely deliver the injection to the subject, It can result in a significant reduction in the spring force required, and a longer duration. For example, the springs present in many known autoinjectors are configured such that conventional injections with a volume in the range of about 0.8-1.5 ml are delivered completely to the subject in 10-15 seconds. In contrast, injector embodiments of the present invention deliver a complete injection of about 0.8-about 1.0 ml in about 1 to about 5 seconds, in some embodiments in about 2 to about 4 seconds, in some embodiments in about 3 seconds. It may have a spring configured to allow. It is believed that this reduction in time would require less time to deliver a complete injection when using the autoinjector embodiments of the present invention, thereby causing the patient to experience less pain, thereby increasing patient compliance.

In addition, in some embodiments the spring material may be selected to allow a reduction in the spring force only over the stroke length of the injection, for example, as shown in FIG. 16. Many known autoinjectors show a decrease in spring force of less than about 20% over a single injection process. In contrast, the injector embodiments of the present invention have at least about 25% over a single injection procedure, in some embodiments from about 25% to about 50% over a single injection procedure, and in some embodiments from about 30% to over a single injection procedure About 50%, and in some embodiments, may be configured to reduce the spring force by about 50% over a single injection procedure.

Spring materials are also selectable and springs can be placed in the injector to prevent the springs from becoming too compressed during packaging and shipping to the end user or patient. This is beneficial because springs that are too compressed for the time spent are over stressed and show a decrease in force over time. For example, many known autoinjectors are packaged such that these springs are compressed to consume most of their shelf life. In packaging in this way, such known autoinjectors will have a reduced spring force over time during the waiting period for use of the autoinjector on the shelf. On the other hand, the injector embodiment of the present invention may have a spring made of a material of sufficient elasticity so that the force decreases over time even in the compressed state, which is fully compressed until injection in the fully assembled injector. It may have a spring configured so as not to be in a closed state. In this way, the injector embodiments of the present invention reduce from about 0% to about 15% of their spring forces over a normal quality life. In some embodiments, the injectors of the present invention are reduced from about 10% to about 12% of their spring forces over a three year quality life.

In some embodiments of a single injector, the injector 12 has a disabling mechanism, such as a locking element, which may be provided with a locking ring 70 that is coupled with the injection mechanism. As shown in FIGS. 6A-6D, the locking ring 70 can be disposed between the sleeve 16 and the needle guard 66, and by interacting with the sleeve 16 and the needle guard 66, the locking ring 70 may allow the needle guard 66 to move only relative to the outer housing 14 via a single injection cycle. This includes movement from the protected position (FIG. 6A) to the dice (FIGS. 6B, 6C), and then back to the protected position under the action of the compression spring 72 force (FIG. 6D). When the needle guard 16 returns to the protective position at the end of the injection cycle, the locking ring is positioned relative to the sleeve and the needle guard to restrain further movement between the sleeve 16 and the needle guard 66, thereby allowing further injection of the injector. At the same time, the needle 24 is safely held in the housing 14 of the injector 12.

As shown in FIGS. 6A-6D, the movement of the needle guard 66 through one locking cycle causes the locking ring 70 to move relative to the sleeve 16 from the spigot to the locked position. The locking ring 70 at the spigot is a device in which the upper arm 71 of the locking ring 70 is engaged with the drug chamber 22, such as a terminal notch 92 formed on the outer surface of the sleeve 16, for example. It is arranged to engage with part of. The engagement of the upper arm 71 in the distal notch 92 keeps the locking ring 70 detachable at the dice. As shown in FIG. 7, the locking ring 70 may be approximately rounded to enclose the quantum chamber 22 directly or indirectly, for example by a sleeve 16 surrounding it. The lock ring 70 further includes a pair of lower arms 73 each having a tab 74 formed at its end. When the lock ring 70 is on the dice, the tab 74 slides into the slot 95 formed in the needle guard 66 such that the needle guard 66 slides through the lock ring 70 through a predetermined distance. It is stored. As the needle guard 66 moves in a dice against the outer housing 14, the needle guard 66 slides over the locking ring 70, with the tab 74 reaching the end of the slot 95. By being pressed inwards, the needle guard 66 continues to move to the dice. Upon reaching the dice, the tabs 74 mate with the holes 96 of the needle guard 66, allowing the lower arms 73 to return to their original positions. At this time, the upper surface of the tab 74 is engaged with the edge of the hole 96, thereby coupling the locking ring 70 to the needle guard (66).

As the needle guard 66 returns to the protective position, the needle guard 66 is pulled distal to the locking ring 70 to allow the upper arm 71 to be separated from the end notch 92. In some embodiments, the inclined surface of the upper arm 71 and the other portion of the injector 12 coupled with the drug chamber 22 by, for example, extending into the distal notch 92 but are forced outwards by distal movement thereto. The upper arm 71 and the end notch 92 are formed in the mating inclined surface so that this contact | abutment may occur. This configuration allows the needle guard 66 to move out of the die as the locking ring 70 moves with it distal to the guard position past the sleeve 16 with the needle guard 66 stationary. .

When the needle guard 66 reaches the protective position, the upper arm 71 moves on the end notch 93 formed in the sleeve 16 so that the upper end of the upper arm 71 is the upper part of the end notch 93. Meshes with face 94. Also in that state, the flange 77 of the lock ring 70 presses the surface 67 of the needle guard, preventing the lock ring 70 from moving to the distal end relative to the lock ring 70. This coupling prevents the locking ring 70 from distally moving relative to the sleeve 16. Since the lock ring 70 is coupled to the needle guard 66 in this configuration and the sleeve 16 is attached to the outer housing 14, the needle guard 66 is locked to the outer housing 14. This prevents the return movement to the dice. This prevents accidental exposure of the needle 24 after use of the injector 12. In other embodiments, other instruments may be used to prevent reuse of the injector or portions thereof. Some embodiments may not employ such a mechanism to reuse the injector. In some embodiments, after the injection of the drug, the next injection can be automatically prevented and prevented from being exposed or contacted with the rest of the instrument, which may remain on a portion of the injector after the injection, such as a needle tip or injection injection nozzle. In addition, it may be prevented or avoided by the structure of the injector 12.

Referring to FIG. 11, the end of an embodiment of a needleless injector is shown. The injector shown may use the device disclosed herein, as described above for needle injector embodiments, but uses a jet nozzle 202 instead of a needle to inject a drug into a subject. The nozzle 202 has a diameter selected to leave the nozzle 202 as a fluid jet stream that is strong enough to penetrate the outer skin layer and lasts to the desired injection depth.

Example

The following examples detail the injection and pharmacokinetics of one or more dangerous agents injected into one or more subjects using embodiments of the injectors disclosed herein. It will be apparent to those skilled in the art that various modifications may be made to both the material and the method without departing from the scope of the disclosure.

Example  One

Pharmacokinetic (PK) analysis was performed to compare and explain the device exposure of dangerous drug methotrexate obtained from female and male Göttingen miniporgs after subcutaneous injection with one of the autoinjectors of the present invention or one of the known hypodermic needles / syringes. It was done.

Both methotrexate and the control article were injected. Administration of test and control articles, blood collection and progress for this study were conducted by Charles River Preclinical Services (Spencerville, OH), under non-FDA compliant good laboratory practice (GLP) conditions. The plasma concentration data shown were made by Research Grade Level 3 liquid chromatography tandem mass spectrometry (LC-MS / MS).

Methotrexate was injected into the mini pigs, alternatively to the same set of animals via subcutaneous injection by either an autoinjector or a needle / syringe. Injections were made on days 1 and 8. Table 3 shows the experimental design of the PK portion of the study.

Injection device Number of animals gender Date ^a Substance Dose level
(Mg / day) Volume
(Ml) Dosage
(Mg / ml) Auto injector 3 cock One Methotrexate injection USP 12.5 0.5 25 3 female 8 Needle / syringe 3 cock 8 Methotrexate injection USP 12.5 0.5 25 3 female One

a: Three identical animals / genders were used on days 1 and 8.

Blood (about 1 mL) samples were collected in K ₂ EDTA containing tubes from all animals according to the schedule shown in Table 4. All samples were processed for plasma prior to analysis for methotrexate and 7-OH metabolite concentrations. Plasma concentration results for 7-OH metabolite did not undergo PK analysis.

Animal count pharmacokinetics (time after administration) -1 day and 2 days Male Female 0 ^a 0.25 0.5 0.75 1 1.5 2 4 6 8 12 24  3 3 × × × × × × × × × × ×

a: sample collected before administration

×: collected sample

The PK profile of each animal was analyzed using non-compartmental analysis of methotrexate plasma concentration data at the target sampling point using free computer software (WinNonlin, version 5.2.1, Pharsight Corp., Mountain View, CA, USA). Characterized by. The model was chosen based on the extravascular route of administration and the plasma matrix. The predosing concentration was assumed to be zero for the purposes of PK parameter evaluation.

The area under the methotrexate plasma concentration-versus-time curve (AUC) was calculated using the linear trapezoidal method (linear interpolation). In the experiment, the terminal elimination phase of the PK profile was identified based on the optimal line using three or more final observed concentration values. The slope of the terminal disappearance phase was calculated using log-linear regression with insignificant concentration data. PK parameters describing the device exposure of the test article in the test device were estimated with observed plasma concentration values (rather than expected), dosing regimen, AUC, and terminal loss phase factor constants (K _el ) for each animal. If the dosing coefficient (R _sq ) of the optimal line was less than 0.800, or indicated that the estimate of AUC exceeded 20% of the total area to infinity, no parameter dependent on the determination of K _el was reported.

Descriptive statistics (mean and standard deviation) were calculated in Microsoft Excel, 2000/2003, for the appropriate numerical data obtained during the study.

As shown in Tables 5 and 6, methotrexate was above the lower limit of quantitation in some samples collected prior to the first and eighth days of administration: male number S5196559 (needle / syringe, day 8, 0.558 ng / ml); Male No. S5196206 (needle / syringe, day 8, 0.222 ng / ml); And female number S5195684 (needle / syringe, day 8, 3.19 ng / ml). From previous samples containing high concentrations of methotrexate, it was attributed to carry over. Methotrexate could be quantified in all post-administration samples, except for 24h samples from males S5196273 and S5196206 after injection with autoinjector (day 1).

Concentration of methotrexate in plasma of Göttingen mini pigs after subcutaneous injection of methotrexate with an autoinjector or syringe

BQL = below the quantitative limit (BQL 0.200ng / ml). BQL concentrations were assumed to be zero values for the mean calculation.

n a = not applicable.

Concentration of methotrexate in plasma of Göttingen mini pigs after subcutaneous injection of methotrexate with an autoinjector or syringe

BQL = below the quantitative limit (BQL 0.200ng / ml). BQL concentrations were assumed to be zero values for the mean calculation.

n a = not applicable.

As shown in Tables 7, 12, 13, and 14, the maximum plasma concentrations of methotrexate were generally observed at the time of initial collection (0.25h) for both devices. Methotrexate concentrations decreased in a clear bixponential fashion. At an estimated time point, the terminal loss half-life of methotrexate ranged from 1.81 to 4.90 hours.

Pharmacokinetic Parameters of Methotrexate in Göttingen Mini-pig Plasma After Subcutaneous Injection of Methotrexate with Autoinjector or Syringe>

a: median reported for T _max

b: No value reported because AUC (O-inf) was above 20% or R _sq was 0.800. Do not count.

As shown in Table 7, Table 8, Figures 14 and 15, the exposure obtained with either the autoinjector or the needle / syringe was very similar.

As shown in Table 7, Figure 13 and Figure 14, although very little trend of greater exposure was observed in males, especially through needle / syringe administration, there was no significant difference in exposure between males and females.

In summary, the pharmacokinetics of methotrexate in plasma was characterized in male and female Göttingen mini pigs after subcutaneous injection of 12.5 mg with either an autoinjector device or a needle / syringe. The maximum concentration of methotrexate was observed almost immediately (0.25 h) after a single dose, and then decreased in a double exponential fashion. The terminal loss half-life of methotrexate ranged from 1.81 to 4.90 hours. The exposure obtained with either the autoinjector or the needle / syringe was similar. There was no noticeable gender difference in PK parameters.

Example  2

Enbrel® SureClik ^™ autoinjector (Immunex Corporation, Thousand Oasks, CA, USA) and HUMIRA® pen (Abbott Laboratories, Abbott, two known conventional autoinjectors) Park, IL, USA) were compared to compare and describe all the spring forces and the time required for complete delivery of the injection solution in the range of 0.68-1.0 ml.

Control articles were injected for this test. The results for two known autoinjectors were averaged. A comparison result is shown in FIG. As shown in Fig. 16, the time required for full delivery of the injection solution to the known autoinjector is 10 seconds, while the time required for full delivery of the injection solution to the autoinjector of the present invention is only 3 seconds. Therefore, users of known autoinjectors must hold their autoinjectors at the injection site for a total of 10 seconds in order to have a complete injection. On the other hand, a user of the autoinjector of the present invention only needs to maintain the autoinjector for 3 seconds at the injection site.

In addition, as shown in FIG. 16, the spring force required to deliver the total injection liquid is reduced by about 50% in 3 seconds for the autoinjector of the present invention. This contrasts with less than about 20% spring force reduction in 10 seconds for known autoinjectors.

As used herein, the term "about" should be understood to refer to both the value and the range of that value. In addition, all numerical ranges herein should be understood to include each entire integer within the range.

While exemplary embodiments of the invention have been disclosed herein, it will be understood that many modifications and other embodiments may be devised by those skilled in the art. Therefore, it is to be understood that the appended claims are intended to cover such modifications and embodiments as fall within the spirit and scope of the invention.

Claims (21)

A container configured to receive a dangerous agent;
An injection outlet member coupled to the container for injecting the dangerous agent;
A launch mechanism configured to launch the hazardous drug from the fluid chamber through the outlet member to inject the dangerous drug;
An energy source coupled to the launching mechanism to perform an injection to power the launching mechanism;
A trigger mechanism coupled to the launch mechanism to operate the launch mechanism; And
A powered injector comprising a therapeutically effective amount of a dangerous agent contained in said container,
The powered injector is configured to inject a therapeutically effective amount of the dangerous agent within about 5 seconds. The method of claim 1,
The dangerous agents are botulinum toxin, injectable gold, 6-mercaptopurine, 6-thioinosine acid, azathioprine, chlorambucil, cyclophosphamide, cytophosphane, cytarabine, fluorouracil, melphalan, Methotrexate, uramustine, anti-cytokine biologicals, cell receptor antagonists, cell receptor analogs, dexamethasone, progesterone, somatostatin, analogs of dexamethasone, analogs of progesterone, analogs of somatostatin, teriparatide, scopolamine, antihypertensive agents, Hypotensive agents, fentanyl, fentanyl citrate, morphine, meperidine, other narcotic analgesics, adalimumab (anti-tissue necrosis factor monoclonal antibody or anti-TNF), anakinra, daclizumab, basiliximab Azathioprine, cyclosporin, tacrolimus, testosterone, estrogen, growth hormone, insulin, thyroid hormone, follicle stimulating hormone (FSH), Phinephrine / adrenaline, gamma-linolenic acid, docosahexanoic acid, arachidonic acid, eicosapentaenoic acid, amobarbital, pentobarbital, secobarbital, phenobarbitol, clonazepam, diazepam, estazolam, flu Nitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam, chlorodiazepoxide, alprazolam, ashbagenda, dubosia hopwood, prosanteria stratiflora, cava ( Piper mettisicum), mandrake, valerian, marijuana, eszopiclone, zaleflon, zolpidem, zodiaclone, diphenhydramine, dimenhydrinate, doxylamine, promethazine, chloral hydrate, dicy Chlomin, Atropine, Ipratropium Bromide, Oxytropium Bromide, Tiotropium, Levodopa, Dopamine, Carbidopa, Bengerazide, Corseralpa, Cobeneldopa, Tolcapone, Entacapone, Bromocrip Teen, Pergolide, pramipexole, rofinirol, pyribedil, cabergoline, apomorphine, lysuride, human growth hormone, erythropoietin, haloperidol, droperidol, chlorpromazine, flufenazine, perfer Phenazine, Prochlorperazine, Thioridazine, Trifluoroferazine, Mesorazine, Ferricazine, Promazine, Triplelupromazine, Levomepromazine, Promethazine, Pimozide, Chlorproticen, Chlorine Pentic sol, flufentic sol, thiotixen, zucopentic sol, clozapine, olazapine, risperidone, quetipine, ziprasidone, amisulfride, acenapine, paliperidone, iloperidone, zotepin, sertindol , Aripiprazole, bifepronox, etanercept, and derivatives of the aforementioned materials and combinations thereof. The method of claim 1,
The dangerous agent is methotrexate. The method of claim 1,
The powered injector is configured to inject a therapeutically effective amount of the dangerous agent within about 4 seconds. The method of claim 1,
The powered injector is configured to inject a therapeutically effective amount of the dangerous agent in about 1 second. The method of claim 1,
The powered injector is configured to inject the dangerous agent at a flow rate of at least about 0.5 ml / sec. The method of claim 6,
The energy source is configured to generate a pressure of at least about 300 psi in the vessel. The method of claim 6,
The jet injector is a needle-mounted jet injector, the injection outlet member having an injection support needle configured to penetrate the outer layer of the patient's skin and deliver the dangerous agent as a jet into the tissue of the patient. The method of claim 6,
The jet injector is a needleless jet injector, the injection outlet member is provided with a needleless nozzle, and the energy source is strong enough to allow the jet injected dangerous agent to penetrate the outer layer of the patient's skin to the depth of injection. Injection device. The method of claim 1,
The dangerous agent is at a concentration of about 7.5 mg / ml to about 150 mg / ml. The method of claim 3,
The injector is a prefilled single-shot injector,
The launch mechanism and energy source are coupled and configured to inject only a single shot of methotrexate,
And the injector comprises a disabling mechanism that disables further injection of the injector after the single shot. A container configured to receive a dangerous agent;
An injection outlet member coupled to the container for injecting the dangerous agent;
A launch mechanism configured to launch the hazardous drug from the fluid chamber through the outlet member to inject the dangerous drug;
An energy source coupled to the launching mechanism for injecting dangerous drugs from the injection outlet by providing power to the launching mechanism;
A trigger mechanism coupled to the launch mechanism to operate the launch mechanism; And
A spray injector comprising a therapeutically effective amount of a dangerous agent contained in said container,
The jet injector is configured to inject a therapeutically effective amount of the dangerous agent at a flow rate of at least about 0.5 ml / sec. The method of claim 12,
The jet injector is configured to inject a therapeutically effective amount of the dangerous agent within about 4 seconds. The method of claim 12,
The jet injector is configured to inject a therapeutically effective amount of the dangerous agent in about 1 second. The method of claim 12,
The jet injector is a needle-mounted jet injector, the injection outlet member having an injection support needle configured to penetrate the outer layer of the patient's skin and deliver the dangerous agent as a jet into the tissue of the patient. The method of claim 12,
The jet injector is a needleless jet injector, the injection outlet member is provided with a needleless nozzle, and the energy source is strong enough to allow the jet injected dangerous agent to penetrate the outer layer of the patient's skin to the depth of injection. Injection device. The method of claim 12,
The dangerous agent is methotrexate. Injectable device for the treatment of inflammatory diseases,
A container configured to receive a dangerous agent;
An injection outlet member coupled to the container for injecting the dangerous agent;
A launch mechanism configured to launch the hazardous drug from the fluid chamber through the outlet member to inject the dangerous drug;
An energy source coupled to the launching mechanism for injecting dangerous drugs from the injection outlet by providing power to the launching mechanism;
A trigger mechanism coupled to the launch mechanism to operate the launch mechanism; And
A spray injector comprising a therapeutically effective amount of a dangerous agent contained in said container,
The risk agent consists of methotrexate, the therapeutically effective amount of methotrexate is sufficient to treat an inflammatory disease,
The jet injector is configured to inject a therapeutically effective amount of methotrexate within about 5 seconds. 19. The method of claim 18,
The inflammatory disease is rheumatoid arthritis injection device. 19. The method of claim 18,
The jet injector is configured to inject a therapeutically effective amount of methotrexate drug within about 4 seconds. 19. The method of claim 18,
The jet injector is configured to inject a therapeutically effective amount of methotrexate in about 1 second.

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